專(zhuān)利名稱(chēng)：用于檢測(cè)卵巢疾病的方法和組合物的制作方法
技術(shù)領(lǐng)域：
本發(fā)明涉及用于檢測(cè)卵巢癌的方法和組合物。
背景技術(shù)：
卵巢癌是導(dǎo)致世界范圍內(nèi)的人群中顯著的發(fā)病率和死亡率的主要原因。根據(jù)來(lái)自美國(guó)癌癥協(xié)會(huì)(American Cancer Society)的數(shù)據(jù)，僅在美國(guó)，據(jù)估計(jì)每年就有23,400個(gè)卵巢癌新病例。另外，每年有13,900個(gè)與卵巢癌-相關(guān)的死亡病例，這使得它在美國(guó)成為女性中占第五位的主要癌癥殺手。因?yàn)?0％-90％的發(fā)生卵巢癌的女性無(wú)該病的家族史，所以研究的努力已經(jīng)集中在研發(fā)在該病的早期過(guò)程中檢測(cè)卵巢癌的檢驗(yàn)和診斷方案。然而，迄今為止尚無(wú)研發(fā)的檢驗(yàn)試驗(yàn)證實(shí)可降低卵巢癌的死亡率。
癌癥的分類(lèi)決定了適宜的治療并且有助于確定預(yù)后。使用公認(rèn)的等級(jí)和病期系統(tǒng)按照組織學(xué)(即″分級(jí)″)和疾病的程度(即″疾病分期″)分類(lèi)卵巢癌。在I級(jí)中，腫瘤組織得到充分分化。在II級(jí)中，腫瘤組織中度充分分化。在III級(jí)中，腫瘤組織分化不足。III級(jí)的預(yù)后不及I級(jí)或II級(jí)。I期一般限于一側(cè)(IA期)或兩側(cè)(IB期)卵巢周?chē)哪抑?，不過(guò)，在某些I期(即IC期)癌癥中，在腹水、腹膜沖洗液中或卵巢表面上可以檢測(cè)到惡性細(xì)胞。II期涉及腫瘤從一側(cè)或兩側(cè)卵巢擴(kuò)散或轉(zhuǎn)移至其它骨盆結(jié)構(gòu)。在IIA期中，腫瘤擴(kuò)散或已經(jīng)轉(zhuǎn)移至子宮、輸卵管或它們兩者。IIB期涉及腫瘤轉(zhuǎn)移至骨盆。IIC期為帶有額外要求的IIA或IIB期，該要求為在腹水、腹膜沖洗液中或卵巢表面上可以檢測(cè)到惡性細(xì)胞。在III期中，腫瘤包括至少一種到達(dá)小腸或網(wǎng)膜的惡性擴(kuò)散，已經(jīng)形成用顯微鏡可見(jiàn)(IIIA期)或肉眼可見(jiàn)(＜2厘米直徑，IIIB期；＞2厘米直徑，IIIC期)大小的盆外腹膜植入物或已經(jīng)轉(zhuǎn)移至腹膜后或腹股溝淋巴結(jié)(IIIC期的交替指示劑)。在IV期中，可以檢測(cè)到遠(yuǎn)距離(即非腹膜)的腫瘤轉(zhuǎn)移灶。
尚不了解卵巢癌不同病期的實(shí)際期限，但是認(rèn)為每個(gè)期限至少約為1年(Richart等，1969，Am.J.Obstet.Gynecol.105386)。預(yù)后隨指定病期的增加而下降。例如，診斷為I、II、III和IV期卵巢癌的患者的5-年存活率分別為80％-95％、57％、25％和8％。目前，約60％以上的卵巢癌在III期或IV期才得到診斷，此時(shí)的預(yù)后處在最差狀態(tài)。
卵巢癌的高死亡率可歸因于在卵巢癌的早期患者中缺乏特異性癥狀，由此使得難以進(jìn)行早期診斷。患有卵巢癌的患者通常出現(xiàn)非特異性的病癥，諸如異常陰道出血、胃腸道癥狀、泌尿道癥狀、下腹痛和泛發(fā)性腹脹。這些患者很少出現(xiàn)類(lèi)腫瘤性癥狀或清楚地表明為卵巢癌的癥狀。由于不存在早期預(yù)兆，所以低于約40％的患有卵巢癌的患者存在I期或II期癌癥。如果可以在早期檢測(cè)到卵巢癌，那么可以顯著提高對(duì)該病的控制，此時(shí)治療一般會(huì)更為有效。
可以通過(guò)從患者中采集常規(guī)的醫(yī)學(xué)史并且通過(guò)進(jìn)行體格檢查、X射線檢查以及化學(xué)和血液學(xué)研究部分診斷卵巢癌。可以預(yù)示卵巢癌的血液學(xué)試驗(yàn)包括分析CA125和DF3蛋白的血清水平和溶血磷脂酸(LPA)的血漿水平。對(duì)卵巢的觸診和超聲技術(shù)，特別是包括陰道內(nèi)超聲和彩色多普勒流動(dòng)超聲技術(shù)可以有助于檢測(cè)卵巢腫瘤和從良性卵巢囊腫分化成卵巢癌。然而，對(duì)卵巢癌的確診一般仍然需要進(jìn)行剖腹探查術(shù)。
作為卵巢癌診斷標(biāo)志的血清CA125水平的在先應(yīng)用表明該方法對(duì)用作一般的檢驗(yàn)方法而言表現(xiàn)出的特異性不足。精確的算法在解釋獲自患者的連續(xù)回顧性樣品中CA125水平中的應(yīng)用提高了該方法的特異性，而不會(huì)將卵巢癌的檢測(cè)變動(dòng)到早期(Skakes，1995，Cancer 762004)。檢驗(yàn)LPA以便檢測(cè)婦科癌癥，包括卵巢癌表現(xiàn)出了約96％的靈敏度和約89％的特異性。然而，基于CA125的檢驗(yàn)方法和基于LPA的檢驗(yàn)方法因在患有非卵巢癌的疾病的患者血清中分別存在CA125和LPA而受到阻礙。例如，已知血清CA125水平與月經(jīng)、妊娠、胃腸和肝臟疾病(例如結(jié)腸炎和肝硬化)、心包炎、腎病和各種非卵巢惡性腫瘤相關(guān)。例如，已知血清LPA受存在的非卵巢婦科惡性腫瘤影響。對(duì)卵巢癌所具有的特異性高于目前對(duì)CA125和LPA的檢驗(yàn)方法的檢驗(yàn)方法可以為廣泛人群提供對(duì)早期卵巢癌的檢驗(yàn)。
還在臨床研究中證實(shí)了經(jīng)陰道的聲象圖測(cè)試不能作為檢驗(yàn)卵巢癌的可靠的方法。例如，在評(píng)價(jià)聲象圖檢驗(yàn)在14,469位無(wú)癥狀女性中的功效中，對(duì)每個(gè)檢測(cè)的侵害性癌癥病例取5200次超聲的平均值(VanNage11等2000，Gynecol.Oncol.77350-356)。在另一項(xiàng)研究中，Liede等同時(shí)使用了經(jīng)陰道的聲象圖檢查和CA125以便篩選處于高危卵巢癌中的女性(2002，J.CHn.Oncol.201570-1577)。Liede等得出結(jié)論，聯(lián)合的檢驗(yàn)方法在降低卵巢癌的發(fā)病率或死亡率中無(wú)效。因此，USPreventive Services Task Force已經(jīng)推薦從定期檢查中排除對(duì)卵巢癌的常規(guī)檢驗(yàn)(Goff，等2004，JAMA 222710)。
新近，已經(jīng)將腫瘤mRNA與正常組織mRNA進(jìn)行了比較以便使用cDNA微陣列鑒定癌組織中的增量調(diào)節(jié)基因(即卵巢癌標(biāo)志)。已經(jīng)通過(guò)這種技術(shù)鑒定了Prostasin、骨橋蛋白、HE4和多種其它標(biāo)志。然而，cDNA微陣列手段的局限在于在腫瘤中的轉(zhuǎn)錄活性不一定準(zhǔn)確地反映出組織中所述蛋白質(zhì)的水平或該蛋白質(zhì)在組織中的活性。例如，僅在肺癌腫瘤中的基因百分比較小表示mRNA與其相應(yīng)蛋白質(zhì)水平之間具有統(tǒng)計(jì)學(xué)顯著的相關(guān)性(Chen等2002，Clin.Cancer Res.82290-2305)。另外，大量翻譯后的改變可以在未在RNA水平上反映出改變的蛋白質(zhì)中發(fā)生。
由于用于檢測(cè)卵巢癌的已知方法的成本以及有限的靈敏度和特異性，所以目前無(wú)法在廣泛人群中進(jìn)行檢驗(yàn)。此外，為診斷對(duì)卵巢癌適應(yīng)征檢驗(yàn)為陽(yáng)性的患者的卵巢癌而進(jìn)行剖腹術(shù)的需要限制了廣泛人群檢驗(yàn)的理想性。因此，對(duì)研發(fā)基于基因或蛋白質(zhì)的卵巢癌標(biāo)志的表達(dá)的更具有靈敏性和特異性的檢驗(yàn)和診斷方法存在迫切需求。
概括地說(shuō)，如果能檢測(cè)出早期卵巢癌，那么患者的存活率和生活質(zhì)量就可以得到改善。因此，對(duì)檢測(cè)卵巢癌，特別是早期卵巢癌的靈敏性和特異性方法存在迫切的需求。

發(fā)明內(nèi)容
提供了用于診斷卵巢癌的組合物和方法。本發(fā)明的方法包括檢測(cè)至少一種生物標(biāo)志在身體樣品中的超表達(dá)，其中檢測(cè)所述的生物標(biāo)志的超表達(dá)可以特異性鑒定預(yù)示卵巢癌的樣品。本發(fā)明的方法可以將預(yù)示卵巢癌的樣品與預(yù)示良性增殖的樣品區(qū)別開(kāi)來(lái)。因此，該方法依賴(lài)于檢測(cè)在卵巢癌情形中選擇性超表達(dá)，而在正常細(xì)胞或未預(yù)示臨床疾病的細(xì)胞中未超表達(dá)的生物標(biāo)志。在具體的實(shí)施方案中，本發(fā)明的方法可有利于診斷早期卵巢癌。
本發(fā)明的生物標(biāo)志為在卵巢癌中選擇性超表達(dá)的蛋白質(zhì)和/或基因。特別關(guān)注的是在早期卵巢癌中超表達(dá)的生物標(biāo)志。生物標(biāo)志包括例如急性期反應(yīng)物(例如蛋白酶抑制劑和炎性蛋白)；脂蛋白；調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)；編程性細(xì)胞死亡調(diào)節(jié)物；結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白。檢測(cè)本發(fā)明生物標(biāo)志基因或蛋白質(zhì)的超表達(dá)能夠區(qū)分預(yù)示卵巢疾病的樣品與正常細(xì)胞或未預(yù)示臨床疾病的細(xì)胞(例如良性增殖)。
可以在蛋白質(zhì)或核酸水平上評(píng)價(jià)生物標(biāo)志的超表達(dá)。在某些實(shí)施方案中，提供了免疫化學(xué)技術(shù)，它們使用抗體檢測(cè)患者血清樣品中生物標(biāo)志蛋白的超表達(dá)。在本發(fā)明的該方面中，使用針對(duì)所關(guān)注的特異性生物標(biāo)志的至少一種抗體。還可以通過(guò)基于核酸的技術(shù)，例如雜交檢測(cè)超表達(dá)。進(jìn)一步提供了包含用于實(shí)施本發(fā)明方法的試劑的試劑盒。
還可以將本發(fā)明的方法與傳統(tǒng)的婦科和血液學(xué)診斷技術(shù)，諸如經(jīng)陰道的聲象圖檢驗(yàn)和CA125血清水平分析聯(lián)用。因此，例如本文提供的免疫化學(xué)方法可以與CA125分析和經(jīng)陰道的聲象圖測(cè)試相結(jié)合，以便保存來(lái)自常規(guī)方法的所有信息。以這種方式，在卵巢癌中選擇性超表達(dá)的生物標(biāo)志的檢測(cè)可以減少使用其它檢驗(yàn)方法觀察到的高度″假陽(yáng)性″和″假陰性″，并且可以有利于大規(guī)模的自動(dòng)化檢驗(yàn)。
發(fā)明詳述本發(fā)明提供了用于鑒定或診斷卵巢癌，特別是早期卵巢癌的組合物和方法。這些方法包括檢測(cè)在卵巢癌中選擇性超表達(dá)的特異性生物標(biāo)志的超表達(dá)。即，本發(fā)明的生物標(biāo)志能夠?qū)㈩A(yù)示卵巢癌的樣品與正常樣品和那些未表示臨床疾病的特征的樣品(例如良性增殖)區(qū)別開(kāi)來(lái)。用于診斷卵巢癌的方法包括檢測(cè)預(yù)示卵巢癌的至少一種生物標(biāo)志在來(lái)自患者的身體樣品，特別是血清樣品中的超表達(dá)。在本發(fā)明的某些方面中，所述的方法能夠檢測(cè)早期卵巢癌。在具體的實(shí)施方案中，抗體和免疫化學(xué)技術(shù)用于檢測(cè)所關(guān)注的生物標(biāo)志的表達(dá)。進(jìn)一步提供了用于實(shí)施本發(fā)明方法的試劑盒。
″診斷卵巢癌″意欲包括，例如診斷或檢測(cè)卵巢癌的存在，監(jiān)測(cè)該疾病的進(jìn)展和鑒定或檢測(cè)預(yù)示卵巢癌的細(xì)胞或樣品。術(shù)語(yǔ)診斷、檢測(cè)和鑒定卵巢癌在本文中可以互換使用。所謂″卵巢癌″意指那些在剖腹探查術(shù)后分類(lèi)為癌癥前病狀、惡性病狀和癌癥(FIGO I-IV期)的疾病?！逶缙诼殉舶迨侵改切┓诸?lèi)為I期或II期癌癥的疾病狀態(tài)。卵巢癌的早期檢測(cè)顯著提高了5-年存活率。
如上所述，由傳統(tǒng)診斷方法誤診的顯著百分比的患者實(shí)際上患有卵巢癌。因此，本發(fā)明的方法能夠確切診斷所有患者群體中的卵巢癌，包括這些″假陽(yáng)性″和″假陰性″病例，并且有利于卵巢癌的早期診斷。卵巢癌在該病的早期得到檢測(cè)改善了患者的預(yù)后和生活質(zhì)量。可以使診斷不依賴(lài)于CA125和經(jīng)陰道的聲象圖狀況，不過(guò)本發(fā)明的方法還可以與這些常規(guī)的診斷檢驗(yàn)技術(shù)聯(lián)用。
本文披露的方法提供了比CA125分析或經(jīng)陰道的聲象圖檢驗(yàn)優(yōu)良的檢測(cè)卵巢癌的方法，并且能夠檢測(cè)早期卵巢癌。在本發(fā)明的具體方面中，本發(fā)明方法的靈敏度和特異性等于或大于CA125或經(jīng)陰道的聲象圖檢驗(yàn)的靈敏度和特異性。本文所用的″特異性″是指本發(fā)明方法可以準(zhǔn)確鑒定通過(guò)剖腹探查術(shù)證實(shí)為非惡性的樣品(即，真陰性)的水平。即，特異性為測(cè)試呈陰性的疾病陰性比例。在臨床研究中，通過(guò)將真陰性的數(shù)量除以真陰性和假陽(yáng)性總和計(jì)算特異性。所謂″靈敏度″意指本發(fā)明方法可以準(zhǔn)確鑒定剖腹術(shù)證實(shí)為卵巢癌陽(yáng)性的樣品(即，真陽(yáng)性)的水平。因此，靈敏度為測(cè)試呈陽(yáng)性的疾病陽(yáng)性的比例。通過(guò)將真陽(yáng)性的數(shù)量除以真陽(yáng)性和假陰性總和計(jì)算靈敏度。披露的用于檢測(cè)卵巢癌的方法的靈敏度至少約為70％，優(yōu)選至少約為80％，更優(yōu)選至少約為90，91，92，93，94，95，96，97，98，99％或99％以上。此外，本發(fā)明方法的特異性?xún)?yōu)選至少約為70％，更優(yōu)選至少約為80，最優(yōu)選至少約為90，91，92，93，94，95，96，97，98，99％或99％以上。
本發(fā)明的生物標(biāo)志包括基因和蛋白質(zhì)。這類(lèi)生物標(biāo)志包括含有編碼該生物標(biāo)志的核酸序列的完整或部分序列或這類(lèi)序列補(bǔ)體的DNA。生物標(biāo)志核酸還包括含有所關(guān)注任何核酸序列的完整或部分序列的RNA。生物標(biāo)志蛋白為由本發(fā)明DNA生物標(biāo)志編碼的或相當(dāng)于本發(fā)明的DNA生物標(biāo)志的蛋白質(zhì)。生物標(biāo)志蛋白包括任何生物標(biāo)志蛋白質(zhì)或多肽類(lèi)的完整或部分氨基酸序列。
″生物標(biāo)志″為任何的基因或蛋白質(zhì)，其在組織或細(xì)胞中的表達(dá)水平與正?；蚪】导?xì)胞或組織中的表達(dá)水平相比得到改變。本發(fā)明的生物標(biāo)志對(duì)卵巢癌具有選擇性。所謂″在卵巢癌中選擇性超表達(dá)″意指所關(guān)注的生物標(biāo)志在卵巢癌中超表達(dá)，但在分類(lèi)為非惡性的、良性的疾病和其它認(rèn)為不是臨床疾病的狀況中不會(huì)超表達(dá)。因此，檢測(cè)本發(fā)明的生物標(biāo)志能夠?qū)㈩A(yù)示卵巢癌的樣品與正常樣品和預(yù)示非惡性和良性增殖的樣品區(qū)別開(kāi)來(lái)。以這種方式，本發(fā)明的方法能夠準(zhǔn)確鑒定卵巢癌，甚至在被傳統(tǒng)診斷方法，諸如經(jīng)陰道的聲象圖檢驗(yàn)錯(cuò)誤地分類(lèi)為正常、非惡性或良性(即″假陰性″)的病例中也是如此。
本發(fā)明的生物標(biāo)志包括如上文所定義的在卵巢癌中選擇性超表達(dá)的任何基因或蛋白質(zhì)。這類(lèi)生物標(biāo)志能夠鑒定與癌癥前、惡性或明顯為癌性的卵巢疾病相關(guān)的患者樣品中的基因或蛋白質(zhì)。盡管預(yù)示卵巢癌的任何生物標(biāo)志都可以用于本發(fā)明，但是在優(yōu)選的實(shí)施方案中，生物標(biāo)志選自急性期反應(yīng)物(例如蛋白酶抑制劑和炎性蛋白)、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白組成的組。此外，在具體的實(shí)施方案中，所述的生物標(biāo)志選自α-1-抗胰蛋白酶、AMBP、鈣粒蛋白B、碳酸酐酶、叢生蛋白、肌動(dòng)蛋白絲切蛋白(非肌肉同種型)、ficolin 2、ficolin 3、凝溶膠蛋白、觸珠蛋白、觸珠蛋白-相關(guān)生物標(biāo)志、血紅素蛋白、間-α-胰蛋白酶抑制劑、肽基脯氨酸順?lè)串悩?gòu)酶A、血漿谷胱甘肽過(guò)氧化物酶、血小板堿性蛋白、血清鐵傳遞蛋白、血清淀粉樣A4蛋白、四連接素、運(yùn)甲狀腺素蛋白、玻連蛋白和鋅-α-2-糖蛋白組成的組。
特別關(guān)注的是在早期卵巢癌中選擇性超表達(dá)的生物標(biāo)志。所謂″在早期卵巢癌中選擇性超表達(dá)″意指所關(guān)注的生物標(biāo)志在I期或II期卵巢癌情形中超表達(dá)，而在正常樣品或分類(lèi)為非惡性、良性的疾病或認(rèn)為是不臨床疾病的其它狀況中不會(huì)超表達(dá)。本領(lǐng)域技術(shù)人員將會(huì)認(rèn)識(shí)到早期卵巢癌生物標(biāo)志包括那些預(yù)示卵巢癌的基因和蛋白質(zhì)，它們最初在I期或II期中超表達(dá)，并且其超表達(dá)持續(xù)貫穿于該病晚期，并且所述的早期卵巢癌生物標(biāo)志還包括僅在I期或II期卵巢癌中超表達(dá)的生物標(biāo)志。檢測(cè)在早期卵巢癌中選擇性超表達(dá)的生物標(biāo)志可以對(duì)卵巢癌進(jìn)行早期檢測(cè)和診斷，且由此可以改善患者的預(yù)后。
急性期反應(yīng)物蛋白為所關(guān)注的生物標(biāo)志，并且包括，例如蛋白酶抑制劑和炎性蛋白。α-1-抗胰蛋白酶為蛋白酶抑制劑，特別是絲氨酸蛋白酶抑制劑。缺乏該酶與肺氣腫和肝病相關(guān)。α-1-抗胰蛋白酶為彈性酶的有效抑制劑并且還對(duì)纖維蛋白溶酶和凝血酶具有中度親和力。該蛋白質(zhì)由位于第14染色體長(zhǎng)臂遠(yuǎn)端上的基因(PI)編碼。
AMBP或α-1-微球蛋白/尿抑胰酶素前體為急性期反應(yīng)物并且在許多生理液中發(fā)現(xiàn)，包括血漿、尿和腦脊液。AMBP作為自由單體存在并且還可以與IgA和清蛋白復(fù)合。
間-α胰蛋白酶抑制劑4(血漿激肽釋放酶-敏感性糖蛋白)看來(lái)也是急性期反應(yīng)物。該蛋白質(zhì)屬于Kunitz-類(lèi)蛋白酶抑制劑家族。不同于該蛋白質(zhì)家族中的其它成員(例如H1、H2和H3)，間-α胰蛋白酶抑制劑4缺乏尿抑胰酶素鏈。
鈣粒蛋白B與炎性細(xì)胞因子相關(guān)并且在浸潤(rùn)單核細(xì)胞和粒細(xì)胞中表達(dá)。鈣粒蛋白B為S100蛋白質(zhì)家族中的成員。S100基因含有2 EF-手鈣結(jié)合基元，已經(jīng)鑒定了至少13個(gè)家族成員，并且它們作為簇群位于染色體Iq21上。鈣粒蛋白B可能在抑制酪蛋白激酶中起作用并且已經(jīng)在囊性纖維化中發(fā)現(xiàn)了該蛋白質(zhì)表達(dá)的改變。
在具體的實(shí)施方案中，本發(fā)明的生物標(biāo)志包括脂質(zhì)降解、交換或蛋白質(zhì)轉(zhuǎn)運(yùn)中涉及的蛋白質(zhì)。載脂蛋白L1為結(jié)合載脂蛋白A-I的分泌的高密度脂蛋白。這種載脂蛋白L家族成員可以在整個(gè)體內(nèi)的脂質(zhì)交換和轉(zhuǎn)運(yùn)以及膽固醇從周?chē)?xì)胞逆行轉(zhuǎn)運(yùn)至肝中起作用。已經(jīng)鑒定了編碼該基因的兩種不同同種型的至少三種轉(zhuǎn)錄物變體。
鋅-α-2-糖蛋白刺激脂肪細(xì)胞中的脂質(zhì)降解并且導(dǎo)致與某些晚期癌癥相關(guān)的脂肪過(guò)度喪失。這種蛋白質(zhì)還可以結(jié)合多不飽和脂肪酸。
血清淀粉樣A蛋白和血清淀粉樣A-4蛋白為HDL復(fù)合物的主要急性期反應(yīng)物和載脂蛋白。這兩種蛋白質(zhì)均由肝表達(dá)并且在血漿中分泌。還關(guān)注調(diào)節(jié)補(bǔ)體系統(tǒng)或細(xì)胞凋亡途徑的蛋白質(zhì)。補(bǔ)體成分C3在活化補(bǔ)體系統(tǒng)中起關(guān)鍵作用。活化C3是經(jīng)典和替代補(bǔ)體活化途徑所需的。存在C3缺乏的患者表現(xiàn)出對(duì)細(xì)菌感染的易感性增加。補(bǔ)體因子H-相關(guān)蛋白2也可能參與調(diào)節(jié)補(bǔ)體系統(tǒng)。補(bǔ)體因子H-相關(guān)蛋白2可以聯(lián)合脂蛋白并且可以在脂質(zhì)代謝中起作用。
Ficolin家族蛋白通過(guò)凝集素途徑活化補(bǔ)體系統(tǒng)。Ficolin家族蛋白的特征在于存在前導(dǎo)肽(即，短的N-末端片段)，隨后是膠原蛋白樣區(qū)和C-末端血纖蛋白原樣結(jié)構(gòu)域。還在其它蛋白質(zhì)中發(fā)現(xiàn)了Ficolin蛋白的膠原蛋白樣和C-末端血纖蛋白原樣結(jié)構(gòu)域，所述的其它蛋白質(zhì)諸如，例如補(bǔ)體蛋白Ciq、結(jié)合腕蛋白和稱(chēng)作膠原凝集素的C-類(lèi)凝集素。在人血清中，存在兩種類(lèi)型的ficolin。由FCN2編碼的Ficolin 2主要在肝中表達(dá)并且已經(jīng)證實(shí)它們具有碳水化合物結(jié)合和調(diào)理活性。已經(jīng)描述了因選擇性剪接和編碼ficolin 2的不同同種型產(chǎn)生的FCN2的四種轉(zhuǎn)錄物變體。剪接變體SVO為最主要的。肝中的FCN2基因轉(zhuǎn)錄物編碼313個(gè)氨基酸的蛋白質(zhì)并且代表了最長(zhǎng)的ficolin 2同種型。Ficolin 3為不耐熱的β-2-巨糖蛋白(macroglycoprotein)并且是ficolin/調(diào)理素p35凝集素家族中的成員。最初基于與來(lái)自患有系統(tǒng)性紅斑狼瘡的患者的血清的反應(yīng)性鑒定的該蛋白質(zhì)，已經(jīng)證實(shí)具有不依賴(lài)于鈣的凝集素活性。該蛋白質(zhì)可以與MASPs和sMAP聯(lián)合活化補(bǔ)體途徑，由此通過(guò)凝集素途徑的活化有助于宿主防御。選擇性剪接在該基因座上發(fā)生并且已經(jīng)鑒定了各自編碼獨(dú)特同種型的兩種變體。
叢生蛋白的功能尚不清楚，但是它與程序性細(xì)胞死亡(編程性細(xì)胞死亡)相關(guān)。叢生蛋白在多種組織中表達(dá)并且可以結(jié)合細(xì)胞、膜和疏水性蛋白質(zhì)。
還關(guān)注結(jié)合血紅素、血紅蛋白或鐵的生物標(biāo)志蛋白。觸珠蛋白在肝中表達(dá)并且與游離的血漿血紅蛋白相結(jié)合。觸珠蛋白可以防止鐵通過(guò)腎丟失并且保護(hù)腎免遭血紅蛋白的損害，同時(shí)還可以使得血紅蛋白易于接近降解酶。觸珠蛋白-相關(guān)蛋白前體也在早期卵巢癌中選擇性超表達(dá)。
血紅素蛋白為將血紅素轉(zhuǎn)運(yùn)至肝而用于分解和鐵回收的血紅素結(jié)合蛋白質(zhì)，此后使游離血紅素蛋白返回到循環(huán)中。血紅素蛋白由肝表達(dá)并且在血漿中分泌。
血清鐵傳遞蛋白為將鐵從腸、網(wǎng)狀內(nèi)皮系統(tǒng)和肝實(shí)質(zhì)細(xì)胞轉(zhuǎn)運(yùn)至體內(nèi)的所有增殖性細(xì)胞的鐵結(jié)合糖蛋白。它具有76.5kDa的近似分子量并且具有同源C和N-末端結(jié)構(gòu)域，它們各自結(jié)合一個(gè)三價(jià)鐵離子。除鐵轉(zhuǎn)運(yùn)功能外，血清鐵傳遞蛋白還可以作為從血清中除去某些有機(jī)物/變應(yīng)原中涉及的粒細(xì)胞/花粉-結(jié)合蛋白(GPBP)起生理作用。構(gòu)成細(xì)胞骨架或參與維持、調(diào)節(jié)或調(diào)制細(xì)胞的細(xì)胞結(jié)構(gòu)的生物標(biāo)志蛋白(即細(xì)胞結(jié)構(gòu)蛋白)也用于實(shí)施本發(fā)明。這類(lèi)細(xì)胞結(jié)構(gòu)蛋白包括，但不限于肌動(dòng)蛋白細(xì)胞骨架蛋白、非膠原性基質(zhì)蛋白和適當(dāng)?shù)鞍踪|(zhì)折疊中涉及的蛋白質(zhì)。肌動(dòng)蛋白絲切蛋白為廣泛分布的胞內(nèi)肌動(dòng)蛋白-調(diào)節(jié)蛋白，它結(jié)合絲狀F-肌動(dòng)蛋白并且使其解聚且以pH-依賴(lài)性方式抑制單體G-肌動(dòng)蛋白聚合。肌動(dòng)蛋白絲切蛋白參與肌動(dòng)蛋白-肌動(dòng)蛋白絲切蛋白從細(xì)胞質(zhì)轉(zhuǎn)移至細(xì)胞核。
凝溶膠蛋白為鈣調(diào)節(jié)的肌動(dòng)蛋白-調(diào)節(jié)蛋白，它結(jié)合肌動(dòng)蛋白單體或絲的正(或帶刺)末端，從而通過(guò)封閉或加冒防止單體交換。凝溶膠蛋白不但促進(jìn)單體裝配成絲(成核)而且切割已經(jīng)形成的絲。
四連接素和玻連蛋白為非膠原性基質(zhì)蛋白。四連接素結(jié)合血纖蛋白原和分離的三環(huán)4并且可能參與包裝指定用于胞吐的分子。在血清和組織中均發(fā)現(xiàn)了玻連蛋白并且它們促進(jìn)細(xì)胞粘著和鋪展，抑制終末溶細(xì)胞補(bǔ)體途徑的膜損傷作用，并且結(jié)合幾種絲氨酸蛋白酶抑制蛋白，即絲氨酸蛋白酶抑制劑。玻連蛋白為分泌的蛋白并且以單鏈形式或通過(guò)二硫鍵彼此結(jié)合的截短的雙鏈形式。
肽基脯氨酸順?lè)串悩?gòu)酶A催化寡肽類(lèi)中脯氨酸的亞胺酸肽鍵的順?lè)串悩?gòu)化并且加速蛋白質(zhì)折疊。它是肽基脯氨酸順?lè)串悩?gòu)酶(PPI酶)家族中的成員。已經(jīng)報(bào)導(dǎo)了對(duì)不同染色體作圖的多個(gè)假基因。已經(jīng)觀察到了編碼兩種不同同種型的三種選擇性剪接的轉(zhuǎn)錄物變體。
催化代謝副產(chǎn)物解毒的酶也包括在本發(fā)明的生物標(biāo)志中。碳酸酐酶I屬于鋅金屬酶的大家族(即碳酸酐酶(CAs))，它們催化二氧化碳的可逆水化。CAs參與多種生物過(guò)程，包括呼吸、鈣化、酸堿平衡、骨吸收和房水、腦脊液、唾液和胃酸的形成。CAs在組織分布及其亞細(xì)胞定位上表現(xiàn)出廣泛的多樣性。CA1與第8染色體上的CA2和CA3基因緊密連鎖，并且CA1編碼主要在紅細(xì)胞中表達(dá)的胞質(zhì)蛋白。也已經(jīng)描述了使用選擇性聚腺苷酸化位點(diǎn)的CA1的轉(zhuǎn)錄物變體。
血漿谷胱甘肽過(guò)氧化物酶催化還原谷胱甘肽對(duì)過(guò)氧化氫、有機(jī)氫過(guò)氧化物和脂質(zhì)過(guò)氧化物的還原并且在防止細(xì)胞遭受氧化性損傷中起作用。已經(jīng)證實(shí)人血漿谷胱甘肽過(guò)氧化物酶為含硒的酶并且表達(dá)看來(lái)是組織特異性的。
所關(guān)注的生物標(biāo)志還包括生長(zhǎng)因子和激素結(jié)合蛋白。血小板堿性蛋白為屬于CXC趨化因子家族的血小板衍生的生長(zhǎng)因子。該生長(zhǎng)因子為有效的化學(xué)引誘物和中性白細(xì)胞激活物。已經(jīng)證實(shí)血小板堿性蛋白可刺激各種不同的細(xì)胞過(guò)程，包括，例如DNA合成、有絲分裂、糖酵解、胞內(nèi)cAMP蓄積、前列腺素E2分泌和透明質(zhì)酸和硫酸化葡糖胺聚糖的合成。它還刺激由滑膜細(xì)胞形成和分泌血纖蛋白原激活物。運(yùn)甲狀腺素蛋白為激素結(jié)合蛋白，更具體地說(shuō)，為可能將甲狀腺素從血流中轉(zhuǎn)運(yùn)至腦的甲狀腺激素結(jié)合蛋白。
盡管已經(jīng)詳細(xì)地討論了上述生物標(biāo)志，但是在卵巢癌中超表達(dá)的任何生物標(biāo)志都可以用于實(shí)施本發(fā)明。在具體的實(shí)施方案中，所關(guān)注的生物標(biāo)志如上文所定義的在早期卵巢癌中選擇性超表達(dá)。
盡管本發(fā)明的方法為檢測(cè)卵巢癌而需要檢測(cè)患者樣品中的至少一種生物標(biāo)志，但是2、3、4、5、6、7、8、9、10或10種以上生物標(biāo)志可以用于實(shí)施本發(fā)明。公認(rèn)檢測(cè)身體樣品中的一種以上生物標(biāo)志可以用于鑒定卵巢癌的情況。因此，在某些實(shí)施方案中，使用兩種或多種生物標(biāo)志，更優(yōu)選兩種或多種互補(bǔ)生物標(biāo)志。所謂″互補(bǔ)″意指檢測(cè)身體樣品中生物標(biāo)志的組合使得能夠成功地鑒定更大百分比的卵巢癌病例，所述百分比高于僅使用一種生物標(biāo)志鑒定的卵巢癌病例的百分比。因此，在某些情況下，可以通過(guò)使用至少兩種生物標(biāo)志對(duì)卵巢癌進(jìn)行更準(zhǔn)確的確定。因此，如果使用至少兩種生物標(biāo)志，那么針對(duì)不同生物標(biāo)志蛋白的至少兩種抗體將用于實(shí)施本文披露的免疫化學(xué)方法?？梢允顾龅目贵w與身體樣品同時(shí)或共同接觸。
在具體的實(shí)施方案中，本發(fā)明的診斷方法包括從患者中采集身體樣品，使該樣品接觸對(duì)所關(guān)注的生物標(biāo)志具有特異性的至少一種抗體，并且檢測(cè)抗體結(jié)合。正如通過(guò)對(duì)抗體結(jié)合檢測(cè)所確定的，認(rèn)為表現(xiàn)出本發(fā)明生物標(biāo)志超表達(dá)的樣品對(duì)卵巢癌是陽(yáng)性的。在優(yōu)選的實(shí)施方案中，所述的身體樣品為血清樣品。在本發(fā)明的某些方面中，所述的樣品為血漿樣品。
所謂″身體樣品″意指任何細(xì)胞、組織或體液的樣品，其中可以檢測(cè)到生物標(biāo)志的表達(dá)。這類(lèi)身體樣品的實(shí)例包括，但不限于血液、淋巴、尿、婦科液體、活檢和汗液?？梢酝ㄟ^(guò)各種技術(shù)，包括，例如通過(guò)刮取或拭抹某一區(qū)域或通過(guò)使用抽吸體液的針頭從患者體內(nèi)獲得身體樣品。用于采集各種身體樣品的方法為本領(lǐng)域眾所周知。在優(yōu)選的實(shí)施方案中，身體樣品包括血清。在一個(gè)實(shí)施方案中，BD VacutainerSSTTM管可以用于采集患者血液以便進(jìn)行血清分析。將含有血液的管倒置以確保血塊激活物添加劑與患者血液混合，并且所得血清在30分鐘內(nèi)準(zhǔn)備就緒。
本文包括本領(lǐng)域中可用于鑒定或檢測(cè)所述生物標(biāo)志的任何方法?？梢栽诤怂崴交虻鞍踪|(zhì)水平上檢測(cè)本發(fā)明生物標(biāo)志的超表達(dá)。為了確定超表達(dá)，可以將待檢驗(yàn)的身體樣品與相應(yīng)的來(lái)源于健康人的身體樣品進(jìn)行比較。即″正?！灞磉_(dá)水平為所述生物標(biāo)志在未患卵巢癌的人體受試者或患者身體樣品中的表達(dá)水平。這類(lèi)樣品可以以標(biāo)準(zhǔn)化形式存在。在某些實(shí)施方案中，確定生物標(biāo)志的超表達(dá)無(wú)需將所述身體樣品與相應(yīng)的來(lái)源于健康人的身體樣品進(jìn)行比較。在這種情況中，所關(guān)注的生物標(biāo)志被超表達(dá)至這樣的程度，即它不需要與來(lái)源于健康人的相應(yīng)身體樣品進(jìn)行比較。
用于檢測(cè)本發(fā)明生物標(biāo)志的方法包括在核酸或蛋白質(zhì)水平上確定生物標(biāo)志的量或存在的任何方法。這類(lèi)方法為本領(lǐng)域眾所周知，并且包括，但不限于蛋白質(zhì)印跡、RNA印跡、DNA印跡、酶聯(lián)免疫吸附測(cè)定(ELISA)、免疫沉淀、免疫熒光、流式細(xì)胞計(jì)量術(shù)、基于珠粒的免疫化學(xué)、免疫化學(xué)、分子印記、核酸適體、核酸雜交技術(shù)、核酸逆轉(zhuǎn)錄法和核酸擴(kuò)增法。在具體的實(shí)施方案中，例如，使用針對(duì)特異性生物標(biāo)志蛋白的抗體在蛋白質(zhì)水平上檢測(cè)生物標(biāo)志的超表達(dá)。這些抗體可以用于各種方法，諸如蛋白質(zhì)印跡、ELISA或免疫沉淀技術(shù)。
在一個(gè)實(shí)施方案中，對(duì)生物標(biāo)志蛋白具有特異性的抗體用于檢測(cè)生物標(biāo)志蛋白在身體樣品中的超表達(dá)。該方法包括從患者中獲得身體樣品，使該身體樣品接觸針對(duì)在卵巢癌中選擇性超表達(dá)的生物標(biāo)志的至少一種抗體，并且檢測(cè)抗體結(jié)合，以便確定所述的生物標(biāo)志是否在患者樣品中超表達(dá)。如上所述，在某些情況下，可以通過(guò)檢測(cè)患者樣品中的一種以上生物標(biāo)志來(lái)獲得對(duì)卵巢癌的更準(zhǔn)確的診斷。因此，在具體的實(shí)施方案中，將針對(duì)兩種不同生物標(biāo)志的至少兩種抗體用于檢測(cè)卵巢癌。如果使用一種以上抗體，那么可以將這些抗體作為單獨(dú)的抗體試劑依次加入到單一樣品中或作為抗體混合物同時(shí)加入?；蛘?，可以將每一單個(gè)抗體加入到來(lái)自相同患者的分開(kāi)的樣品中并且采集所得數(shù)據(jù)。本領(lǐng)域技術(shù)人員將會(huì)認(rèn)識(shí)到可以通過(guò)手動(dòng)或以自動(dòng)化方式進(jìn)行本文所述的免疫化學(xué)方法。
在本發(fā)明優(yōu)選的免疫化學(xué)方法中，將雙抗體或″夾心式″ELISA用于檢測(cè)患者樣品中生物標(biāo)志的超表達(dá)。這類(lèi)″夾心式″或″兩位點(diǎn)″免疫測(cè)定法為本領(lǐng)域中公知的。例如，參見(jiàn)Current Protocols in Immunology.Indirect Antibody Sandwich ELISA to Detect Soluble Antigens，JohnWiley & Sons，1991。在本發(fā)明的該方面中，使用對(duì)單一生物標(biāo)志上的兩個(gè)不同抗原位點(diǎn)具有特異性的兩種抗體。所謂″不同抗原位點(diǎn)″意指抗體對(duì)所關(guān)注的生物標(biāo)志蛋白上的不同位點(diǎn)具有特異性，使得一種抗體與所述生物標(biāo)志蛋白的結(jié)合不會(huì)顯著干擾另一種抗體與所述生物標(biāo)志蛋白的結(jié)合。將稱(chēng)作″俘獲抗體″的第一種抗體固定在固相支持體上或與之結(jié)合。例如，可以使針對(duì)所關(guān)注的生物標(biāo)志的俘獲抗體與微量滴定板孔、珠粒、小池或其它反應(yīng)容器共價(jià)結(jié)合或非共價(jià)結(jié)合。在一個(gè)優(yōu)選的實(shí)施方案中，使俘獲抗體與微量滴定板孔結(jié)合。用于使抗體與固相支持體結(jié)合的方法為本領(lǐng)域中公知的。使身體樣品，特別是血清樣品接觸固相支持體并且使其與結(jié)合的俘獲抗體復(fù)合。除去未結(jié)合的樣品并且將稱(chēng)作″檢測(cè)抗體″的第二種抗體加入到固相基質(zhì)上。該檢測(cè)抗體對(duì)所關(guān)注的生物標(biāo)志上的不同抗原位點(diǎn)具有特異性并且與提供可檢測(cè)信號(hào)的物質(zhì)偶聯(lián)或被該物質(zhì)標(biāo)志。這類(lèi)抗體標(biāo)志為本領(lǐng)域眾所周知的并且包括各種酶、輔基、熒光物質(zhì)、發(fā)光物質(zhì)、生物發(fā)光物質(zhì)和放射性物質(zhì)。在與檢測(cè)抗體一起孵育后，除去未結(jié)合的樣品并且通過(guò)對(duì)與固相支持體結(jié)合的標(biāo)志的檢測(cè)抗體進(jìn)行定量來(lái)確定生物標(biāo)志的表達(dá)水平。本領(lǐng)域技術(shù)人員將會(huì)認(rèn)識(shí)到可以如上所述使所述的俘獲和檢測(cè)抗體依次或同時(shí)與身體樣品接觸。此外，可以在使樣品與固定的俘獲抗體接觸前，先將檢測(cè)抗體與身體樣品一起孵育。
用于通過(guò)使用可檢測(cè)標(biāo)志檢測(cè)抗體結(jié)合的技術(shù)為本領(lǐng)域眾所周知。例如，可以通過(guò)使用化學(xué)試劑檢測(cè)抗體結(jié)合，所述的化學(xué)試劑可以產(chǎn)生對(duì)應(yīng)于抗體結(jié)合水平和由此對(duì)應(yīng)于生物標(biāo)志表達(dá)水平的可檢測(cè)信號(hào)。在某些實(shí)施方案中，使檢測(cè)抗體與酶，特別是催化抗原-抗體結(jié)合位點(diǎn)上的色原體沉積的酶偶聯(lián)。特別關(guān)注的酶包括，但不限于辣根過(guò)氧化物酶(HRP)和堿性磷酸酶(AP)。市售抗體檢測(cè)系統(tǒng)也可以用于實(shí)施本發(fā)明。
上述免疫化學(xué)方法和方式意指典型的而非限制性的，因?yàn)橐话愣裕梢岳斫馊魏蔚拿庖呋瘜W(xué)方法或方式均可以用于本發(fā)明。
術(shù)語(yǔ)″抗體″廣泛包括抗體的天然存在形式和重組抗體，諸如單鏈抗體、嵌合和人源化抗體以及多特異性抗體和上述所有抗體的片段和衍生物，所述的片段和衍生物帶有至少一個(gè)抗原結(jié)合位點(diǎn)?？贵w衍生物可以包括與抗體綴合的蛋白質(zhì)或化學(xué)部分。
″抗體″和″免疫球蛋白″(Igs)為具有相同結(jié)構(gòu)特征的糖蛋白。盡管抗體表現(xiàn)出對(duì)抗原的結(jié)合特異性，但是免疫球蛋白包括抗體和缺乏抗原特異性的其它抗體樣分子。例如，后一類(lèi)型的多肽類(lèi)由淋巴系統(tǒng)以低水平產(chǎn)生并且由骨髓瘤以增加的水平產(chǎn)生。
術(shù)語(yǔ)″抗體″以最廣泛的含義使用并且包括完全裝配的抗體、可以結(jié)合抗原的抗體片段(例如，F(xiàn)ab′、F′(ab)2、Fv、單鏈抗體、雙抗體)和包括上述抗體的重組肽類(lèi)。
本文所用的術(shù)語(yǔ)″單克隆抗體″是指獲自基本上同源抗體群體的抗體，即包括該群體的各個(gè)抗體除可以以最少量存在的可能的天然存在突變外均相同。
″抗體片段″包括完整抗體的一部分，優(yōu)選完整抗體的抗原結(jié)合區(qū)或可變區(qū)。抗體片段的實(shí)例包括Fab、Fab′、F(ab′)2和Fv片段；雙抗體；線性抗體(Zapata等(1995)Protein Eng.8(10)1057-1062)；單鏈抗體分子；和由抗體片段形成的多特異性抗體?？贵w的木瓜蛋白酶消化產(chǎn)生兩種相同的各自含有單一抗原結(jié)合位點(diǎn)的抗原結(jié)合片段，稱(chēng)作″Fab″片段，和殘余″Fc″片段，其名稱(chēng)反映出其易于結(jié)晶35的能力。木瓜蛋白酶處理產(chǎn)生帶有兩個(gè)抗原結(jié)合位點(diǎn)的F(ab′)2片段并且仍然能夠交聯(lián)抗原。
″Fv″為含有完全抗原識(shí)別和結(jié)合位點(diǎn)的最小抗體片段。在雙鏈Fv種類(lèi)中，該區(qū)由非共價(jià)緊密結(jié)合的一個(gè)重鏈和一個(gè)輕鏈可變區(qū)的二聚體組成。在單鏈Fv種類(lèi)中，一個(gè)重鏈和一個(gè)輕鏈可變區(qū)可以通過(guò)柔性肽接頭共價(jià)連接，使得輕鏈和重鏈可以以與雙鏈Fv種類(lèi)類(lèi)似的″二聚″結(jié)構(gòu)形式結(jié)合。各可變區(qū)的三個(gè)CDRs正是以這種構(gòu)型相互作用來(lái)限定VH-VL二聚體表面上的抗原結(jié)合位點(diǎn)。六個(gè)CDRs共同賦予抗體抗原結(jié)合特異性。然而，甚至單一可變區(qū)(或僅包括三個(gè)對(duì)抗原具有特異性的CDRs的Fv的一半)也具有識(shí)別和結(jié)合抗原的能力，不過(guò)，在親和力方面低于完整結(jié)合位點(diǎn)。
Fab片段還含有輕鏈恒定區(qū)和重鏈的第一恒定區(qū)(CH1)。Fab片段與Fab′片段的不同之處在于在重鏈CH1結(jié)構(gòu)域的羧基末端添加了幾個(gè)殘基，包括來(lái)自抗體絞鏈區(qū)的一個(gè)或多個(gè)半胱氨酸。Fab′-SH在本文中是對(duì)其中恒定區(qū)的半胱氨酸殘基帶有游離巰基的Fab′的命名。F(ab′)2抗體片段最初作為Fab′片段對(duì)產(chǎn)生，在它們之間帶有鉸鏈半胱氨酸。
可以通過(guò)用生物標(biāo)志蛋白免疫原給合適的受試者(例如雞、兔、山羊、小鼠或其它哺乳動(dòng)物)免疫接種來(lái)制備多克隆抗體?？梢噪S著時(shí)間的變化通過(guò)標(biāo)準(zhǔn)技術(shù)，諸如借助于使用固定化生物標(biāo)志蛋白的ELISA來(lái)監(jiān)測(cè)經(jīng)免疫接種受試者的抗體滴度。在免疫接種后的適當(dāng)時(shí)間，例如在抗體滴度最高時(shí)，可以從受試者中獲取產(chǎn)生抗體的細(xì)胞并且用于通過(guò)標(biāo)準(zhǔn)技術(shù)制備單克隆抗體，所述的標(biāo)準(zhǔn)技術(shù)諸如最初由Kohler和Milstein(1975)在Nature 256495-497中所述的雜交瘤技術(shù)；人B細(xì)胞雜交瘤技術(shù)(Kozbor等(1983)Immunol Today 472)；EBV-雜交瘤技術(shù)(Cole等(1985)，Monoclonal Antibodies and Cancer Therapy，ed.Reisfeld和Sell(Alan R.Liss，Inc.，New York，NY)，pp.77-96)或三源雜交瘤技術(shù)。用于生產(chǎn)雜交瘤的技術(shù)為眾所周知的{一般參見(jiàn)Coligan等，eds.(1994)Current Protocols in Immunology(JohnWiley & Sons，Inc.，New York，NY)；Galfre等(1977)Nature26655052；Kenneth(1980)，Monoclonal AntibodiesA New DimensionIn Biological Analyses(Plenum Publishing Corp.，NY；和Lerner(1981)Yale J.Biol.Med.，54387-402)。
作為制備分泌單克隆抗體的雜交瘤的備選方法，可以鑒定單克隆抗體并且通過(guò)用生物標(biāo)志蛋白篩選重組免疫球蛋白文庫(kù)(例如，抗體噬菌體展示文庫(kù))分離，由此分離結(jié)合所述生物標(biāo)志蛋白的免疫球蛋白文庫(kù)成員。用于產(chǎn)生和篩選噬菌體展示文庫(kù)的試劑盒為市場(chǎng)上可買(mǎi)到的(例如the Pharmacia Recombinant Phage Antibody System，商品目錄號(hào)27-9400-01；和the Stra tagene SurfZAP9 Phage Display Kit，商品目錄號(hào)240612)。另外，適用于產(chǎn)生和篩選抗體展示文庫(kù)的方法和試劑的實(shí)例可以在下列文獻(xiàn)中找到例如美國(guó)專(zhuān)利US 5,223,409；PCT公開(kāi)號(hào)WO 92/18619；WO 91/17271；WO 92/20791；WO 92/15679；93/01288；WO 92/0104 7；WO 92/09690；和WO 90/02809；Fuchs等(1991)Bio/Technology 91370-1372；Hay等(1992)Hum.Antibod.Hybridomas381-85；Huse等(1989)Science 2 461275-1281；Griffiths等(1993)EMBO J.12725-734。
用于制備單克隆抗體的另一種備選方法可以在通過(guò)蛋白質(zhì)組學(xué)技術(shù)鑒定了與早期卵巢癌相關(guān)的蛋白后進(jìn)行。在鑒定后，為了獲得所表達(dá)的序列標(biāo)志信息而檢索DNA數(shù)據(jù)庫(kù)，以便確定是否存在該蛋白質(zhì)的選擇性轉(zhuǎn)錄物。常規(guī)的核酸雜交或擴(kuò)增方法可以用于驗(yàn)證腫瘤組織中存在基因轉(zhuǎn)錄物。由于已經(jīng)通過(guò)蛋白質(zhì)組學(xué)技術(shù)鑒定了該蛋白質(zhì)，所以基因轉(zhuǎn)錄物存在于腫瘤組織中的可能性較大。一旦驗(yàn)證了其存在，那么就可以在合適的細(xì)胞表達(dá)系統(tǒng)中克隆和表達(dá)所關(guān)注的基因，并且將所得特異性蛋白質(zhì)純化達(dá)到均勻性。信號(hào)序列可以用于促進(jìn)分泌和分離生物標(biāo)志蛋白。信號(hào)序列的典型特征在于疏水氨基酸核心一般在一種或多種切割情況下從分泌過(guò)程中的成熟蛋白中切割下來(lái)。在一個(gè)實(shí)施方案中，可以使編碼信號(hào)序列的核酸序列在表達(dá)載體中可操作地與所關(guān)注的蛋白質(zhì)，諸如生物標(biāo)志蛋白或其片段連接。信號(hào)序列指導(dǎo)該蛋白質(zhì)分泌，諸如從其中轉(zhuǎn)入了表達(dá)載體的真核宿主中分泌，并且該信號(hào)序列隨后或同時(shí)被切割下來(lái)。然后易于通過(guò)本領(lǐng)域公認(rèn)的方法從胞外培養(yǎng)基中純化該蛋白質(zhì)?；蛘?，可以使用有利于純化的序列，諸如借助于GST結(jié)構(gòu)域使所述的信號(hào)序列與所關(guān)注的蛋白質(zhì)連接。
如上文所述，可以通過(guò)使抗體與可檢測(cè)物質(zhì)偶聯(lián)促進(jìn)抗體結(jié)合的檢測(cè)?？蓹z測(cè)物質(zhì)的實(shí)例包括各種酶、輔基、熒光物質(zhì)、發(fā)光物質(zhì)、生物發(fā)光物質(zhì)和放射性物質(zhì)。合適的酶的實(shí)例包括辣根過(guò)氧化物酶、堿性磷酸酶、β-半乳糖苷酶或乙酰膽堿酯酶；合適的輔基復(fù)合物的實(shí)例包括鏈霉抗生物素/生物素和抗生物素蛋白/生物素；合適的熒光物質(zhì)的實(shí)例包括傘形酮、熒光素、異硫氰酸熒光素、若丹明、二氯三嗪基胺熒光素、丹磺酰氯或藻紅蛋白；發(fā)光物質(zhì)的實(shí)例包括魯米諾；生物發(fā)光物質(zhì)的實(shí)例包括螢光素酶、螢光素和水母發(fā)光蛋白；且合適的放射性物質(zhì)的實(shí)例包括125I、131I、35S或3H。
選擇對(duì)所關(guān)注的生物標(biāo)志蛋白具有高度特異性的抗體用于實(shí)施本發(fā)明。用于制備抗體和篩選合適的抗體的方法為本領(lǐng)域眾所周知的。例如，參見(jiàn)Celis，ed.(在印刷中)Cell Biology & Laboratory Handbook，3rd edition(Academic Press，New York)，將該文獻(xiàn)完整地引入本文作為參考。在某些實(shí)施方案中，針對(duì)特異性生物標(biāo)志蛋白的市售抗體可以用于實(shí)施本發(fā)明。在優(yōu)選的實(shí)施方案中，考慮到結(jié)合特異性而根據(jù)最終樣品類(lèi)型(即，血清制品)來(lái)選擇抗體。
在本發(fā)明的某些方面中，通過(guò)多步驟篩選方法選擇和純化針對(duì)所關(guān)注的特異性生物標(biāo)志的抗體。在具體的實(shí)施方案中，篩選多雜交瘤(polydoma)以便鑒定具有所需特異性和敏感性特征的生物標(biāo)志特異性抗體。本文所用的″多雜交瘤″是指多個(gè)雜交瘤。一般在多孔組織培養(yǎng)平板中提供本發(fā)明的多雜交瘤。在最初的抗體篩選步驟中，產(chǎn)生了腫瘤組織微陣列，它包括多個(gè)正常的、I級(jí)(充分分化的)、II級(jí)(中度充分分化的)、III級(jí)(分化不足的)樣品。用于在單一載玻片上產(chǎn)生多種組織陣列的方法和設(shè)備，諸如ChemiconAdvanced Tissue Arrayer為本領(lǐng)域中公知的。例如，參見(jiàn)美國(guó)專(zhuān)利US4,820,504。檢測(cè)來(lái)自含有多雜交瘤的各孔的未稀釋的上清液以便使用標(biāo)準(zhǔn)免疫組織化學(xué)技術(shù)進(jìn)行陽(yáng)性染色。在這一最初的篩選步驟中，背景非特異性結(jié)合基本上忽略不計(jì)。選擇產(chǎn)生多雜交瘤的陽(yáng)性結(jié)果并且用于第二階段的抗體篩選。
在第二個(gè)篩選步驟中，使陽(yáng)性多雜交瘤經(jīng)歷有限的稀釋過(guò)程。檢測(cè)所得的未篩選抗體以便使用標(biāo)準(zhǔn)免疫組織化學(xué)技術(shù)對(duì)I、II或III級(jí)樣品進(jìn)行陽(yáng)性染色。在該步驟，背景染色具有相關(guān)性并且選擇僅對(duì)異常細(xì)胞(即，癌細(xì)胞)染色為陽(yáng)性的候選多雜交瘤用于進(jìn)一步分析。
為了鑒定可以將正常樣品與預(yù)示卵巢癌(即，I級(jí)和I級(jí)以上)的樣品區(qū)別開(kāi)來(lái)的抗體，產(chǎn)生疾病組的組織微陣列。這種組織微陣列一般包括多個(gè)正常和I、II和III級(jí)樣品。將標(biāo)準(zhǔn)免疫組織化學(xué)技術(shù)僅用于檢測(cè)對(duì)預(yù)示卵巢癌疾病的樣品(即，I級(jí)和I級(jí)以上樣品)染色為特異性陽(yáng)性的候選多雜交瘤。選擇產(chǎn)生陽(yáng)性結(jié)果和最小背景染色的多雜交瘤用于進(jìn)一步分析。
將陽(yáng)性染色的培養(yǎng)物制備成各個(gè)克隆以便選擇各個(gè)候選單克隆抗體。用于分離各個(gè)克隆的方法為本領(lǐng)域中眾所周知的。使用上文所述的腫瘤和疾病組的組織微陣列檢測(cè)來(lái)自包括未純化抗體的各克隆的上清液，以便對(duì)I、II或III級(jí)樣品進(jìn)行特異性染色。選擇表現(xiàn)出卵巢疾病樣品(即，I級(jí)和I級(jí)以上)染色為陽(yáng)性、其它細(xì)胞類(lèi)型(即，正常樣品)染色程度最低和很少背景的候選抗體用于純化和進(jìn)一步分析。通過(guò)親和吸收色譜法純化抗體的方法為本領(lǐng)域中眾所周知的。
為了鑒定展示出對(duì)卵巢癌樣品最大限度的特異性染色和血清樣品中最小限度的背景非特異性染色的抗體，使用本發(fā)明的免疫化學(xué)技術(shù)，特別是上文所述的″夾心式″ELIS檢測(cè)在上述基于免疫組織化學(xué)的篩選方法中分離和純化的候選抗體。
具體地，將所關(guān)注的純化抗體用于檢測(cè)來(lái)自I、II、III和TV期卵巢癌患者的統(tǒng)計(jì)學(xué)顯著數(shù)量的血清樣品。如本文所述通過(guò)免疫化學(xué)方法分析樣品并且基于對(duì)特定生物標(biāo)志為陽(yáng)性抗體染色將它們分類(lèi)為卵巢癌陽(yáng)性、陰性或不確定的。計(jì)算各抗體的敏感性、特異性、陽(yáng)性預(yù)測(cè)值和陰性預(yù)測(cè)值。選擇表現(xiàn)出對(duì)卵巢癌血清樣品最大限度的特異性染色與最小限度的背景(即，最大信噪比)的抗體用于本發(fā)明。
鑒定合適的抗體導(dǎo)致信噪比增加和該測(cè)定的臨床效用增加。所用的測(cè)定方式和樣品類(lèi)型是選擇合適的抗體中的關(guān)鍵因素。在免疫組織化學(xué)方式中產(chǎn)生最大信噪比的生物標(biāo)志抗體可能也無(wú)法在免疫化學(xué)測(cè)定法，諸如ELISA測(cè)定法中起作用。例如，分泌的生物標(biāo)志蛋白可能無(wú)法以準(zhǔn)確地反映出相同蛋白質(zhì)在血清中的水平的水平存在于組織樣品中。另外，血清樣品包括許多可能干擾抗體與所關(guān)注的生物標(biāo)志結(jié)合的蛋白質(zhì)，并且在抗體篩選過(guò)程中必須考慮到與這些干擾蛋白相關(guān)的潛在問(wèn)題，因此，抗體選擇需要提前考慮所用的測(cè)定方式和最終樣品的類(lèi)型。
本領(lǐng)域技術(shù)人員將會(huì)認(rèn)識(shí)到需要抗體滴度和檢測(cè)化學(xué)的最優(yōu)化以便使特定抗體的信噪比達(dá)到最大值。必須確定使與本發(fā)明生物標(biāo)志的特異性結(jié)合增加到最大限度而使非特異性結(jié)合(或″背景″)減小到最低限度的抗體濃度。在特定的實(shí)施方案中，通過(guò)最初對(duì)福爾馬林固定的石蠟包埋的正常和卵巢癌組織樣品測(cè)試各種抗體稀釋液來(lái)確定用于來(lái)自患者的血清制品的合適的抗體滴度。首先對(duì)福爾馬林固定的石蠟包埋的正常和卵巢癌組織樣品確定最佳抗體濃度和檢測(cè)化學(xué)條件。使抗體滴度和檢測(cè)條件最優(yōu)化的試驗(yàn)設(shè)計(jì)是標(biāo)準(zhǔn)的并且完全在本領(lǐng)域技術(shù)人員的日常工作能力范圍之內(nèi)的。在確定了適于固定的組織樣品的最佳條件后，將各抗體在相同條件下用于血清制品中。某些抗體需要額外的優(yōu)化以便減少背景染色和/或增加血清樣品中染色的特異性和靈敏性。
此外，本領(lǐng)域技術(shù)人員將會(huì)認(rèn)識(shí)到用于實(shí)施本發(fā)明方法的特定抗體的濃度根據(jù)諸如結(jié)合時(shí)間、抗體對(duì)生物標(biāo)志蛋白的特異性水平和測(cè)試的身體樣品的類(lèi)型這類(lèi)因素的不同而改變。而且，當(dāng)使用多個(gè)抗體時(shí)，所需的濃度可能受到將這些抗體施用于樣品的次序的影響，即，是作為混合物同時(shí)，還是作為單獨(dú)的抗體試劑依次施用于樣品。此外，還必須使用于顯現(xiàn)抗體與所關(guān)注的生物標(biāo)志結(jié)合的檢測(cè)化學(xué)最優(yōu)化以便產(chǎn)生所需的信噪比。
在其它實(shí)施方案中，在核酸水平上檢測(cè)所關(guān)注的生物標(biāo)志的表達(dá)。用于評(píng)價(jià)表達(dá)的基于核酸的技術(shù)為本領(lǐng)域中眾所周知的，并且包括例如，確定身體樣品中生物標(biāo)志mRNA的水平。許多表達(dá)檢測(cè)方法使用分離的RNA。不根據(jù)mRNA的分離作出選擇的任何RNA分離技術(shù)都可以用于從卵巢細(xì)胞中純化RNA(例如，參見(jiàn)Ausubel等，ed.，Current Protocolsin Molecular Biology，John Wiley & Sons，New York 1987-1999)。另外，易于使用本領(lǐng)域技術(shù)人員眾所周知的技術(shù)，諸如，例如Chomczynski的單步驟RNA分離方法(1989，美國(guó)專(zhuān)利US4,843,155)處理大量的組織樣品。
術(shù)語(yǔ)″探針″是指能夠選擇性結(jié)合具體指定的靶生物分子，例如由生物標(biāo)志編碼或?qū)?yīng)于該生物標(biāo)志的核苷酸轉(zhuǎn)錄物或蛋白質(zhì)的任何分子。探針可以由本領(lǐng)域技術(shù)人員合成或來(lái)源于合適的生物制品。可以具體設(shè)計(jì)探針以便被標(biāo)志。可以用作探針的分子的實(shí)例包括，但不限于RNA、DNA、蛋白質(zhì)、抗體和有機(jī)分子。
分離的mRNA可以用于雜交或擴(kuò)增試驗(yàn)，包括，但不限于DNA或RNA分析、聚合酶鏈反應(yīng)分析和探針陣列。用于檢測(cè)mRNA水平的一種方法包括使分離的mRNA接觸可以與由所檢測(cè)的基因編碼的mRNA雜交的核酸分子(探針)。例如，該核酸探針可以為全長(zhǎng)cDNA或其部分，諸如至少7，15，30，50，100，250或500個(gè)核苷酸長(zhǎng)度的并且足以在嚴(yán)格條件下與編碼本發(fā)明生物標(biāo)志的mRNA或基因組DNA雜交的寡核苷酸。mRNA與探針雜交表明所述的生物標(biāo)志得到表達(dá)。
在一個(gè)實(shí)施方案中，例如，通過(guò)在瓊脂糖凝膠上運(yùn)行分離的mRNA且將mRNA從該凝膠中轉(zhuǎn)移至膜，諸如硝化纖維素上將mRNA固定在固相表面上并且與探針接觸。在一個(gè)備選的實(shí)施方案中，將探針固定在固相表面上并且例如，在Affymetrix基因芯片陣列中使mRNA與探針接觸。本領(lǐng)域技術(shù)人員易于采用已知的mRNA檢測(cè)方法用于檢測(cè)由本發(fā)明生物標(biāo)志編碼的mRNA的水平。
用于確定樣品中生物標(biāo)志mRNA水平的備選方法包括核酸擴(kuò)增過(guò)程，例如通過(guò)RT-PCR(在Mullis，1987，美國(guó)專(zhuān)利US 4,683,202中所述的實(shí)驗(yàn)實(shí)施方案)、連接酶鏈反應(yīng)(Barany，1991，Proc.Natl.Acad.Sci.USA，88189-193)、自動(dòng)維持序列擴(kuò)增(Guatelli等，1990，Proc.Natl.Acad.Sci.USA 871874-1878)、轉(zhuǎn)錄擴(kuò)增系統(tǒng)(Kwoh等，1989，Proc.Natl.Acad.Sci.USA 861173-1177)、Q-β復(fù)制酶(Lizardi等，1988，Bio/Technology 61197)、滾環(huán)復(fù)制(Lizardi等，美國(guó)專(zhuān)利US5,854,033)或任何其它核酸擴(kuò)增方法，隨后使用本領(lǐng)域技術(shù)人員眾所周知的技術(shù)檢測(cè)擴(kuò)增的分子。這些檢測(cè)方案尤其適用于檢測(cè)核酸分子，條件是這類(lèi)分子以極低數(shù)量存在。在本發(fā)明具體的方面中，通過(guò)定量熒光RT-PCR(即，TaqManSystem)評(píng)價(jià)生物標(biāo)志表達(dá)。
可以使用膜印跡(諸如用于雜交分析，諸如RNA印跡、DNA印跡、斑點(diǎn)印跡等)或微孔、樣品管、凝膠、珠粒或纖維(或包含結(jié)合的核酸的任何固相支持體)監(jiān)測(cè)RNA的生物標(biāo)志表達(dá)水平。參見(jiàn)美國(guó)專(zhuān)利US5,770,722、US 5,874,219、US 5,744,305、US 5,677,195和US5,445,934，將這些文獻(xiàn)引入本文作為參考。檢測(cè)生物標(biāo)志表達(dá)還可以包括使用在溶液中的核酸探針。
在本發(fā)明的一個(gè)實(shí)施方案中，將微陣列用于檢測(cè)生物標(biāo)志表達(dá)。微陣列特別適合于該目的，因?yàn)樵诓煌瑢?shí)驗(yàn)之間具有再現(xiàn)性。DNA微陣列提供了一種同時(shí)測(cè)定大量基因表達(dá)水平的方法。每個(gè)陣列由結(jié)合在固相支持體上的可再現(xiàn)模式的俘獲探針組成。使標(biāo)志的RNA或DNA在該陣列上與互補(bǔ)探針雜交且然后通過(guò)激光掃描進(jìn)行檢測(cè)。確定每個(gè)探針在陣列上的雜交強(qiáng)度并且將其轉(zhuǎn)化成代表相對(duì)基因表達(dá)水平的定量值。參見(jiàn)美國(guó)專(zhuān)利US 6,040,138、US 5,800,992、US 6,020,135、US 6,033,860和US 6,344,316，將這些文獻(xiàn)引入本文作為參考。高密度寡核苷酸陣列特別可用于確定樣品中大量RNA的基因表達(dá)概況。
使用機(jī)械合成方法合成這些陣列的技術(shù)描述在例如美國(guó)專(zhuān)利US5,384,261中，對(duì)所有實(shí)用場(chǎng)合來(lái)說(shuō)，將該文獻(xiàn)完整地引入本文作為參考。盡管優(yōu)選平面陣列表面，但是可以在實(shí)際上任何形狀的表面乃至多個(gè)表面上形成陣列。陣列可以為珠粒、凝膠、聚合物表面、諸如光導(dǎo)纖維這類(lèi)纖維、玻璃或任何其它合適的襯底上的肽類(lèi)或核酸，參見(jiàn)美國(guó)專(zhuān)利US 5,770,358、US 5,789,162、US 5,708,153、US6,040,193和US5,800,992，對(duì)所有實(shí)用場(chǎng)合來(lái)說(shuō)，將這些文獻(xiàn)各自完整地引入本文作為參考?？梢砸阅軌蜻M(jìn)行診斷或包括一切的裝置的其它操作的方式包裝陣列。例如，參見(jiàn)美國(guó)專(zhuān)利US 5,856,174和US 5,922,591，將這兩篇文獻(xiàn)引入本文作為參考。
在一種方法中，將分離自樣品的總mRNA轉(zhuǎn)化成標(biāo)志的cRNA且然后與寡核苷酸陣列雜交。將每種樣品與單獨(dú)的陣列雜交?？梢詤⒄沾嬖谟谠撽嚵猩虾驮摌悠分械暮线m的對(duì)照物計(jì)算相對(duì)轉(zhuǎn)錄水平。
進(jìn)一步提供了用于實(shí)施本發(fā)明方法的試劑盒。所謂″試劑盒″意指用于特異性檢測(cè)本發(fā)明生物標(biāo)志表達(dá)的任何制品(例如，包裝或容器)，它包含至少一種試劑，例如，抗體、核酸探針等?？梢詫⒃撛噭┖凶鳛橛糜趯?shí)施本發(fā)明方法的一套用具促銷(xiāo)、配銷(xiāo)或銷(xiāo)售。另外，這些試劑盒可以含有描述該試劑盒及其使用方法的產(chǎn)品說(shuō)明書(shū)。在容器內(nèi)，諸如密封容器或塑膠封袋中可以配置任何或所有的試劑盒試劑，所述的容器可以避免所述試劑受到外部環(huán)境的影響。
在一個(gè)具體的實(shí)施方案中，本發(fā)明的免疫細(xì)胞化學(xué)試劑盒另外包含至少兩種試劑，例如抗體，以便特異性檢測(cè)至少兩種不同生物標(biāo)志的表達(dá)。在試劑盒中可以將每種抗體作為單獨(dú)的試劑或作為包括所有針對(duì)所關(guān)注的不同生物標(biāo)志的抗體的抗體混合物提供。
在一個(gè)優(yōu)選的實(shí)施方案中，提供了用于實(shí)施本發(fā)明免疫化學(xué)方法，特別是″夾心式″ELISA技術(shù)的試劑盒。這類(lèi)試劑盒與手動(dòng)和自動(dòng)免疫化學(xué)技術(shù)相適應(yīng)。這些試劑盒包含至少一種針對(duì)所關(guān)注的生物標(biāo)志的初級(jí)俘獲抗體、對(duì)所述生物標(biāo)志上的獨(dú)特抗原位點(diǎn)具有特異性的標(biāo)志的二次檢測(cè)抗體和用于檢測(cè)與所述生物標(biāo)志結(jié)合的抗體的化學(xué)藥品?？梢砸匀芤旱男问教峁┏跫?jí)俘獲抗體，以便隨后與固相支持體結(jié)合?；蛘撸梢詫⒁呀?jīng)與固相支持體，諸如珠粒或微量滴定平板孔結(jié)合的俘獲抗體配置在試劑盒中。檢測(cè)抗原-抗體結(jié)合的任何化學(xué)藥品都可以用于實(shí)施本發(fā)明。在某些實(shí)施方案中，使二次檢測(cè)抗體與催化底物色度轉(zhuǎn)變的酶綴合。這類(lèi)酶和使用它們檢測(cè)抗體結(jié)合的技術(shù)為本領(lǐng)域中眾所周知的。在一個(gè)優(yōu)選的實(shí)施方案中，試劑盒包含與HRP綴合的二次檢測(cè)抗體?？梢赃M(jìn)一步提供與該綴合酶相容的底物，特別是色原(例如，就HRP-標(biāo)志的二次檢測(cè)抗體而言為四甲基聯(lián)苯胺)和諸如硫酸這類(lèi)溶液，用于終止酶促反應(yīng)。在具體的實(shí)施方案中，用于檢測(cè)抗體結(jié)合的化學(xué)藥品包括商購(gòu)試劑和試劑盒。
在另一個(gè)實(shí)施方案中，本發(fā)明的″夾心式″ELISA試劑盒包含用于檢測(cè)至少兩種不同的所關(guān)注的生物標(biāo)志的抗體。這類(lèi)試劑盒包含至少兩種初級(jí)俘獲抗體和針對(duì)不同生物標(biāo)志的兩種二次檢測(cè)抗體?？梢詫⒎@抗體作為單獨(dú)的試劑或作為針對(duì)所關(guān)注的不同生物標(biāo)志的所有抗體的混合物提供。
在試劑盒中可以包括陽(yáng)性和/或陰性對(duì)照品以便證實(shí)用于本發(fā)明的試劑的活性和正確使用。對(duì)照品可以包括已知對(duì)存在所關(guān)注的生物標(biāo)志呈陽(yáng)性或陰性的樣品，諸如組織切片，固定在載玻片上的細(xì)胞等。在一個(gè)具體的實(shí)施方案中，陽(yáng)性對(duì)照為包含所關(guān)注的生物標(biāo)志蛋白的溶液。對(duì)照品的設(shè)計(jì)和使用是標(biāo)準(zhǔn)的并且完全在本領(lǐng)域技術(shù)人員的日常工作能力范圍之內(nèi)。
在其它實(shí)施方案中，進(jìn)一步提供了用于鑒定卵巢癌的包括在核酸水平上檢測(cè)生物標(biāo)志超表達(dá)的試劑盒。例如，這類(lèi)試劑盒包含至少一種特異性結(jié)合生物標(biāo)志核酸或其片段的核酸探針。在具體的實(shí)施方案中，該試劑盒包含至少兩種與不同生物標(biāo)志核酸雜交的核酸探針。
本領(lǐng)域技術(shù)人員將會(huì)認(rèn)識(shí)到可以由技術(shù)人員實(shí)施本發(fā)明方法的任何或所有步驟，或者以自動(dòng)化方式進(jìn)行這些步驟。因此，可以使身體樣品制備、樣品染色和生物標(biāo)志表達(dá)檢測(cè)的步驟自動(dòng)化。在某些實(shí)施方案中，可以將本發(fā)明的方法與傳統(tǒng)的卵巢癌檢驗(yàn)技術(shù)聯(lián)用。例如，可以將本發(fā)明的免疫化學(xué)技術(shù)與常規(guī)的CA125血清分析或經(jīng)陰道的聲象圖檢驗(yàn)相結(jié)合，以便保存來(lái)自常規(guī)方法的所有信息。以這種方式檢測(cè)生物標(biāo)志可以降低CA125檢驗(yàn)的高假陽(yáng)性率，降低經(jīng)陰道的聲象圖檢驗(yàn)的高假陰性率并且可以有利于大規(guī)模的自動(dòng)化檢驗(yàn)。此外，本發(fā)明的方法通過(guò)提供有益于常規(guī)的廣泛人群檢驗(yàn)的診斷試驗(yàn)而能夠早期檢測(cè)卵巢癌。
文章中的″一種″在本文中使用時(shí)是指一種或一種以上(即至少一種)文章中的合乎語(yǔ)法的對(duì)象。作為實(shí)例，″一種成分″意指一種或多種成分。
在本說(shuō)明書(shū)的上下文中，措詞″包括″應(yīng)理解為意指包含所述的成分、整數(shù)或步驟或成分、整數(shù)或步驟組，但不排除任何其它成分、整數(shù)或步驟或成分、整數(shù)或步驟組。
具體實(shí)施例方式
提供下列實(shí)施例是為了解釋?zhuān)鴽Q非起限定作用實(shí)驗(yàn)實(shí)施例1用于鑒定預(yù)示卵巢癌的生物標(biāo)志的血清樣品的SELDI-TOFMS分析材料和方法
使用Ciphergen Biosystems方案和來(lái)自Ciphergen Biosystems的血清分級(jí)分離試劑盒K100-0007以及采集的由冷凍正常人血清，即NHS收集物1和卵巢癌血清，即OCS收集物2組成的樣品(參見(jiàn)各血清樣品數(shù)據(jù)的表1)進(jìn)行血清樣品的手動(dòng)分級(jí)分離。
為了對(duì)血清進(jìn)行分級(jí)分離，融化NHS收集物1和OCS收集物2，使其達(dá)到環(huán)境溫度并且在冷室內(nèi)(4℃)離心(14,000xRCF)20分鐘。將4×20μl每份樣品的等分部分轉(zhuǎn)入Nunc微量滴定平板#249952的4xV底孔內(nèi)。向各孔中轉(zhuǎn)入30μlU9緩沖液(9M脲、2％CHAPS、50mM Tris-HCl，pH9)，隨后在4℃下使用IKA-MTS混合器(設(shè)定為600)將平板振搖20分鐘。振搖后，將50μl處理的樣品從V底平板孔轉(zhuǎn)至含有水合的QCeramic HyperD F吸附樹(shù)脂的過(guò)濾平板(Nunc，Silent Screen平板w/liprodyne膜，#255980)的單獨(dú)的孔中。然后用50μl洗滌緩沖液1(含有0.1％辛基吡喃葡糖苷的50mM Tris-HCl，pH 9)快速洗滌V底平板的孔并且轉(zhuǎn)至已經(jīng)接收了第一種50μl處理的樣品的相同過(guò)濾平板的相應(yīng)孔中。將過(guò)濾平板在4℃下混合30分鐘。然后借助于多頭抽真空裝置在收集平板中收集級(jí)分1的樣品(對(duì)每一樣品類(lèi)型而言為4×100μl)。將新鮮的洗滌緩沖液1(100μl)加入到過(guò)濾平板中的樹(shù)脂中且隨后在RT下混合10分鐘。然后通過(guò)真空將每份緩沖液1的洗滌樣品收集入已經(jīng)接收了第一種100μl洗滌緩沖液1的相同收集平板孔中。這些級(jí)分1樣品代表了合并的流通量和pH9的洗脫液。
通過(guò)下列步驟收集級(jí)分2首先將100μl洗滌緩沖液2(含有0.1％OGP的50mM HEPES，pH7)加入到樹(shù)脂孔中，在RT下混合10分鐘，且隨后在真空下將其從上述使用的平板中收集入單獨(dú)的收集平板中。向相同的樹(shù)脂孔中再次加入100μl洗滌緩沖液2，隨后混合并且在真空下收集入已經(jīng)接收了第一種100μl洗滌緩沖液2的相同孔中。這些級(jí)分2樣品含有pH7的洗脫液。
使用下列緩沖液重復(fù)上述級(jí)分2的過(guò)程級(jí)分3，洗滌緩沖液3(含有0.1％OGP的100mM乙酸鈉，pH5)級(jí)分4，洗滌緩沖液4(含有0.1％OGP的50mM乙酸鈉，pH4)
級(jí)分5，洗滌緩沖液5(含有0.1％OGP的50mM檸檬酸鈉，pH3)級(jí)分6，洗滌緩沖液6(33.3異丙醇/16.7％乙腈/0.1％TFA)。
將含有級(jí)分1-6的收集平板儲(chǔ)存在-80℃下過(guò)夜，此后進(jìn)行結(jié)合分析。
SELDI-TOF MS結(jié)合分析使用生物處理器評(píng)價(jià)4個(gè)NHS和4個(gè)OCS樣品各自的級(jí)分1-6與CM-10、固定化金屬親和俘獲(IMAC)-30和H50芯片(陣列為8)的結(jié)合。因此，將每種芯片類(lèi)型中為8的單一陣列用于每種級(jí)分(即，4/NHS級(jí)分，4/OCS級(jí)分)。首先使用100mM CuSO4將IMAC-30芯片活化10分鐘，隨后用HPLC級(jí)水洗滌3次。然后用特異性結(jié)合緩沖液洗滌陣列(3X)，此后接觸級(jí)分(即，CM-10，100mM乙酸鈉，pH4；IMAC-30，100mM磷酸鈉，pH 7+0.5M NaCl；H50，10％乙腈(ACN)+0.1％三氟乙酸(TFA))。每個(gè)芯片點(diǎn)接受75μl其各自的結(jié)合緩沖液，隨后接受25μl的特定級(jí)分1-6(1/4稀釋)。將生物處理器置于振蕩器上1小時(shí)。
在每個(gè)洗滌步驟時(shí)，將陣列使用150μl其各自的結(jié)合緩沖液洗滌(3×)，同時(shí)振搖10分鐘。最后，用HPLCH2O快速洗滌陣列并且風(fēng)干。在50％ACN和0.05％TFA中新近制備芥子酸并且將1.5μl點(diǎn)在各芯片表面上，干燥并且立即在Ciphergen SELDI儀上分析。儀器設(shè)定如下高質(zhì)量至200kDa；激光強(qiáng)度在200；檢測(cè)器靈敏度在9，且質(zhì)量偏轉(zhuǎn)器在10kDa。使蛋白質(zhì)標(biāo)準(zhǔn)品(C100-0007)以自動(dòng)校準(zhǔn)方式運(yùn)行并且用作樣品分子量的參比物。
結(jié)果CM-10(弱陽(yáng)離子交換劑)蛋白質(zhì)概況分析級(jí)分4和6在與這種芯片結(jié)合的蛋白質(zhì)方面最受關(guān)注。特別是，級(jí)分4具有兩種主要的種類(lèi)，表現(xiàn)為在OCS中高于在NHS中，具有的分子量(MW)為28kDa和13.9kDa(數(shù)據(jù)未顯示)。此外，OCS樣品具有較不顯著的峰，它們?cè)贛W為17.4 kDa、15.8 kDa和15.1kDa時(shí)也升高(數(shù)據(jù)未顯示)。應(yīng)當(dāng)注意28kDa在激肽釋放酶蛋白的范圍內(nèi)。級(jí)分6值得注意的方面在于在NHS與OCS之間觀察到的蛋白質(zhì)差異均在＜10kDa的MW范圍內(nèi)(數(shù)據(jù)未顯示)。另外，在這種分布型中，在66kDa處樣品人血清清蛋白峰(即，帶單電荷和雙電荷的兩個(gè)種類(lèi))在NHS和OCS樣品中均大致相等。
IMAC-30蛋白質(zhì)概況分析使用這種芯片在其對(duì)具有56.3kDa、28.1-28.3 kDa和14-14.1 kDaMW的蛋白質(zhì)的差別展示(在OCS中增量調(diào)節(jié))中級(jí)分6是最引人注目的(數(shù)據(jù)未顯示)。約為56、28和14kDa的MW分別為標(biāo)志FLJ10546、激肽釋放酶和HE4的大小范圍。在兩種樣品中均觀察到了在66kDa的人血清清蛋白。
H50(疏水性)蛋白質(zhì)概況分析由這種芯片表面差別展示的所有蛋白質(zhì)都是針對(duì)大部分低MW(即，＜10kDa)的，但級(jí)分4除外，它還展示出28kDa和17.5kDa峰(在OCS中增量調(diào)節(jié))(數(shù)據(jù)未顯示)。兩種蛋白質(zhì)(7.0和7.5kDa)與NHS相比在OCS中減量調(diào)節(jié)，而3種蛋白質(zhì)(6.4、6.6、6.8kDa)與NHS相比在OCS中增量調(diào)節(jié)。在8.1kDa處的一種蛋白質(zhì)在NHS和OCS中都表現(xiàn)出相同的水平(數(shù)據(jù)未顯示)。
實(shí)施例2使用蛋白質(zhì)組學(xué)技術(shù)在血清樣品中鑒定卵巢癌生物標(biāo)志材料和方法正常和卵巢癌患者血清樣品獲自幾個(gè)商品供應(yīng)商(Uniglobe，Raseda，CA；Diagnostic Support Services，West Yarmouth，MA；Impa th-BCP，F(xiàn)ranklin，MA；ProMedDx，Norton，MA)并且將它們貯存在-80℃下至使用為止。表2中概括了血清樣品的商業(yè)來(lái)源和個(gè)人捐獻(xiàn)者人口統(tǒng)計(jì)信息以及卵巢癌患者的病期。通過(guò)合并等體積的包含各收集物的各個(gè)血清樣品來(lái)制備血清收集物(參見(jiàn)表1)。使用標(biāo)準(zhǔn)試劑盒(ProteoPrep Blue Albumin Depletion Kit，Sigma-Aldrich Co.，St.Louis，MO)，通過(guò)耗盡清蛋白和IgG或通過(guò)使用Q HyperD F珠粒，即一種陰離子交換樹(shù)脂(血清分級(jí)分離試劑盒K100-0007，CiphergenBiosystems，F(xiàn)remont，CA)分級(jí)分離來(lái)降低血清樣品的復(fù)雜性。將通過(guò)SELDI-TOF MS(Ciphergen Biosys tems)顯示出卵巢與正常(對(duì)照)血清之間的差別質(zhì)量指紋分析的陰離子交換級(jí)分使用4個(gè)體積的冷丙酮進(jìn)一步進(jìn)行蛋白質(zhì)沉淀。通過(guò)重構(gòu)丙酮沉淀的蛋白質(zhì)顆?；蛲ㄟ^(guò)將清蛋白/IgG-耗盡的血清稀釋入含有8 M脲、2％CHAPS、50mM二硫蘇糖醇、0.2％兩性電解質(zhì)和溴酚藍(lán)(BioRad Laboratories，Inc.，Hercules，CA)的標(biāo)準(zhǔn)緩沖液來(lái)制備用于2-D凝膠電泳的樣品。在緩沖液中的脲得到顯著稀釋的情況下，加入固定硫脲以使合并的脲/硫脲濃度恢復(fù)到8摩爾。
如實(shí)施例1中所述，通過(guò)SELDI-TOF MS，使用CM-10(弱陽(yáng)離子交換劑)、IMAC-30(金屬螯合劑；使用CuSO4活化)和H50(疏水表面)芯片分析血清級(jí)分，此后進(jìn)行2-D凝膠電泳。在結(jié)合血清級(jí)分后，洗滌芯片，風(fēng)干且然后用在50％ACN和0.05％TFA中制備的芥子酸涂敷。然后通過(guò)SELDI-TOF分析芯片。將含有細(xì)胞色素C、肌紅蛋白、碳酸酐酶、烯醇酶、BSA和牛IgG的溶液用作峰值分子量測(cè)定的標(biāo)準(zhǔn)品。
2-D凝膠電泳就等電聚焦(IEF)而言，使用Protean IEF Cell(BioRad Laboratories)將處理的血清樣品在低電壓條件下主動(dòng)加樣于等電聚焦條帶(固定化pH梯度(IPG)條帶，BioRad Laboratories，Inc.)上12小時(shí)。IPG條帶長(zhǎng)11或17cm并且具有3-10或4-7的pH范圍。
然后使用預(yù)先設(shè)定的線性電壓斜線上升程序?qū)υ偎系纳蠘拥腎P條帶進(jìn)行等電聚焦。將500伏特的保持步驟用于不在實(shí)際聚焦步驟結(jié)束時(shí)即刻操作的IPG條帶，以便防止聚焦的蛋白質(zhì)擴(kuò)散。將聚焦的條帶包埋在0.5％瓊脂糖覆蓋層中，然后在小的預(yù)制的4-20％或10-20％丙烯酰胺凝膠(BioRad″標(biāo)準(zhǔn)″凝膠)或大的預(yù)制的10％丙烯酰胺凝膠(BioRadLaboratories″ProteanII″凝膠)上以第二維進(jìn)行電泳。在室溫下和200V的恒定電壓下進(jìn)行電泳～45分鐘(小凝膠)或以25mA/凝膠的恒定電流進(jìn)行電泳～4.5小時(shí)(大凝膠)。將凝膠固定并且使用市售銀染色試劑盒(Silver Stain Plus，BioRad Labora tories，Inc.)進(jìn)行染色。
2-D凝膠成像比較和對(duì)切下斑點(diǎn)的選擇將凝膠置于曝光箱(lightbox)上并且使用Olympus Camedia C-4000 ZOOM數(shù)碼照相機(jī)成像。將數(shù)字圖像在大小方面校準(zhǔn)、色化(紅色為正常血清收集物，藍(lán)色為卵巢癌血清收集物)并且使用hp臺(tái)式噴墨6127打印機(jī)(Hewlett-Packard)打印在hp高級(jí)噴墨透明薄膜上。用手將透明薄膜置于高架投影儀上并且目視檢查斑點(diǎn)(蛋白質(zhì))分布和圖式的變化。將強(qiáng)度改變或存在于一種樣品，而不存在于另一種樣品中的相應(yīng)斑點(diǎn)切下作為凝膠塞，將其送至外部實(shí)驗(yàn)室(Jan Enghild，University of Aarhus，Denmark)，并且如下所述處理用于鑒定蛋白質(zhì)種類(lèi)。將主要重點(diǎn)放在斑點(diǎn)上，這些斑點(diǎn)1)存在于卵巢樣品中而不存在于正常樣品中或2)在卵巢樣品中具有明顯更大的強(qiáng)度。
通過(guò)MALDI或MS/MS鑒定切下的斑點(diǎn)使用胰蛋白酶將切下的凝膠斑點(diǎn)在37℃下消化過(guò)夜。提取肽類(lèi)且然后脫鹽，此后施用于MALDI靶上并且分析。使用Q-Tof Ultima Global儀(Micromass/waters Corp.，Manchester，U.K.)獲取MALDI-TOF MS或MS/MS數(shù)據(jù)。使用聚乙二醇混合物(1.7mg/ml的PEG200、PEG400、PEG600、PEG1000和PEG2000和在50％(v/v)乙腈中的0.28mg/ml NaI)在m/z 50-3000范圍內(nèi)校準(zhǔn)質(zhì)譜儀。使用glu-血纖維蛋白肽B(MW＝1570.6774)(Sigma)作為鎖定質(zhì)量(lock mass)校準(zhǔn)每一光譜。
為了肽的指紋分析，在800-3000m/z范圍內(nèi)以陽(yáng)離子模式獲取質(zhì)譜。將肽類(lèi)的質(zhì)量表用于使用檢索引擎Mascot軟件(Matrix sciences，London，U.K.)(REF_1)檢索局域Mascot服務(wù)器上的SwissProt/TrEMBL或NCBInr蛋白質(zhì)數(shù)據(jù)庫(kù)。使用50ppm的肽質(zhì)量容限、半胱氨酸殘基的脲基甲基修飾進(jìn)行檢索，并且允許單遺漏的胰蛋白酶切割。僅如通過(guò)Mascot概率分析定義的顯著采樣數(shù)且具有至少5個(gè)匹配的肽質(zhì)量是可接受的。通常，肽質(zhì)量的精確度在10ppm范圍內(nèi)。
對(duì)未通過(guò)肽指紋分析鑒定的蛋白質(zhì)實(shí)施串聯(lián)質(zhì)譜法。選擇豐富的MS先驅(qū)離子并且獲取MS/MS數(shù)據(jù)。將氬氣用作碰撞氣體且碎裂所需的碰撞能根據(jù)肽質(zhì)量的不同在50-120伏特之間的范圍內(nèi)變化。通過(guò)使MS先驅(qū)離子定位至其獲自MS的m/z來(lái)校準(zhǔn)MS/MS數(shù)據(jù)。將所得片段化肽類(lèi)的質(zhì)量表用于使用檢索引擎Mascot軟件(Matrix Sciences，London，U.K.)(REF_1)檢索蛋白質(zhì)數(shù)據(jù)庫(kù)。使用2Da的肽質(zhì)量容限、0.8Da的MS/MS離子質(zhì)量容限、半胱氨酸殘基的脲基甲基修飾和至多一個(gè)遺漏的切割進(jìn)行檢索。就全部鑒定而言，使用人蛋白質(zhì)數(shù)據(jù)庫(kù)。
結(jié)果將所得數(shù)據(jù)分成5個(gè)不同的組。這種分類(lèi)基于分析的血清收集物的特征和用于每組的降低樣品復(fù)雜性的方法(表2)。
總之，從切下的凝膠斑點(diǎn)的胰蛋白酶消化物中鑒定了大量蛋白質(zhì)。盡管表現(xiàn)了許多功能分類(lèi)，但是認(rèn)為大部分鑒定的蛋白質(zhì)一般在人血清和血漿中具有中等豐度。這與可以根據(jù)對(duì)電泳前已經(jīng)耗盡了清蛋白和免疫球蛋白G級(jí)分的血清的2-D分析預(yù)測(cè)的結(jié)果一致。
從陽(yáng)性鑒定的蛋白質(zhì)斑點(diǎn)列表中，將那些認(rèn)為在卵巢癌中得到增量調(diào)節(jié)的蛋白質(zhì)斑點(diǎn)列在表3中。在來(lái)自各數(shù)據(jù)組的正常與卵巢樣品之間的2-D凝膠圖像比較中觀測(cè)到各個(gè)增量調(diào)節(jié)的蛋白質(zhì)斑點(diǎn)(數(shù)據(jù)未顯示)。
表表1.各血清樣品數(shù)據(jù)


UNK-未知N/A-不適用表2.凝膠數(shù)據(jù)組

AEX使用Q HyperD F珠粒的陰離子交換表3.通過(guò)2-D凝膠電泳鑒定為在卵巢癌中增量調(diào)節(jié)的蛋白質(zhì)

本說(shuō)明書(shū)中提及的所有出版物和專(zhuān)利申請(qǐng)表明了本發(fā)明所屬領(lǐng)域的技術(shù)人員的水平。將所有出版物和專(zhuān)利申請(qǐng)引入本文作為參考，其程度與將各出版物或?qū)＠暾?qǐng)明確和個(gè)別引入作為參考的程度相同。
盡管為清楚理解的目的已經(jīng)通過(guò)解釋和實(shí)施例在一定程度上詳細(xì)描述了上述本發(fā)明，但是顯而易見(jiàn)，可以在附加實(shí)施方案的范圍內(nèi)進(jìn)行某些改變和變更。
序列表<110>Beyer，Wayne F.
Venetta，Thomas M.
Groelke，John W.
Blaesius，Rainer H.
<120>檢測(cè)卵巢疾病的方法和組合物<130>46143/294851<150>60/586,856<151>2004-07-09<160>52<170>FastSEQ for Windows Version 4.0<210>1<211>1584<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(233)...(1489)<400>1aagctgtaca ctgcccaggc aaagcgtccg ggcagcgtag gcgggcgact cagatcccag 60ccagtggact tagcccctgt ttgctcctcc gataactggg gtgaccttgg ttaatattca 120ccagcagcct cccccgttgc ccctctggat ccactgctta aatacggacg aggacagggc 180cctgtctcct cagcttcagg caccaccact gacctgggac agtgaatcga ca atg ccg 238Met Pro1tct tct gtc tcg tgg ggc atc ctc ctg ctg gca ggc ctg tgc tgc ctg 286Ser Ser Val Ser Trp Gly Ile Leu Leu Leu Ala Gly Leu Cys Cys Leu5 10 15gtc cct gtc tcc ctg gct gag gat ccc cag gga gat gct gcc cag aag 334
Val Pro Val Ser Leu Ala Glu Asp Pro Gln Gly Asp Ala Ala Gln Lys20 25 30aca gat aca tcc cac cat gat cag gat cac cca acc ttc aac aag atc 382Thr Asp Thr Ser His His Asp Gln Asp His Pro Thr Phe Asn Lys Ile35 40 45 50acc ccc aac ctg gct gag ttc gcc ttc agc cta tac cgc cag ctg gca 430Thr Pro Asn Leu Ala Glu Phe Ala Phe Ser Leu Tyr Arg Gln Leu Ala55 60 65cac cag tcc aac agc acc aat atc ttc ttc tcc cca gtg agc atc gct 478His Gln Ser Asn Ser Thr Asn Ile Phe Phe Ser Pro Val Ser Ile Ala70 75 80aca gcc ttt gca atg ctc tcc ctg ggg acc aag gct gac act cac gat 526Thr Ala Phe Ala Met Leu Ser Leu Gly Thr Lys Ala Asp Thr His Asp85 90 95gaa atc ctg gag ggc ctg aat ttc aac ctc acg gag att ccg gag gct 574Glu Ile Leu Glu Gly Leu Asn Phe Asn Leu Thr Glu Ile Pro Glu Ala100 105 110cag atc cat gaa ggc ttc cag gaa ctc ctc cgt acc ctc aac cag cca 622Gln Ile His Glu Gly Phe Gln Glu Leu Leu Arg Thr Leu Asn Gln Pro115 120 125 130gac agc cag ctc cag ctg acc acc ggc aat ggc ttg ttc ctc agc gag 670Asp Ser Gln Leu Gln Leu Thr Thr Gly Asn Gly Leu Phe Leu Ser Glu135 140 145ggc ctg aag cta gtg gat aag ttt ttg gag gat gtt aaa aag ttg tac 718Gly Leu Lys Leu Val Asp Lys Phe Leu Glu Asp Val Lys Lys Leu Tyr150 155 160cac tca gaa gcc ttc act gtc aac ttc ggg gac acc gaa gag gcc aag 766His Ser Glu Ala Phe Thr Val Asn Phe Gly Asp Thr Glu Glu Ala Lys165 170 175aaa cag atc aac gat tac gtg gag aag ggt act caa ggg aaa att gtg 814Lys Gln Ile Asn Asp Tyr Val Glu Lys Gly Thr Gln Gly Lys Ile Val180 185 190gat ttg gtc aag gag ctt gac aga gac aca gtt ttt gct ctg gtg aat 862
Asp Leu Val Lys Glu Leu Asp Arg Asp Thr Val Phe Ala Leu Val Asn195 200 205 210tac atc ttc ttt aaa ggc aaa tgg gag aga ccc ttt gaa gtc aag gac 910Tyr Ile Phe Phe Lys Gly Lys Trp Glu Arg Pro Phe Glu Val Lys Asp215 220 225acc gag gaa gag gac ttc cac gtg gac cag gtg acc acc gtg aag gtg 958Thr Glu Glu Glu Asp Phe His Val Asp Gln Val Thr Thr Val Lys Val230 235 240cct atg atg aag cgt tta ggc atg ttt aac atc cag cac tgt aag aag 1006Pro Met Met Lys Arg Leu Gly Met Phe Asn Ile Gln His Cys Lys Lys245 250 255ctg tcc agc tgg gtg ctg ctg atg aaa tac ctg ggc aat gcc acc gcc 1054Leu Ser Ser Trp Val Leu Leu Met Lys Tyr Leu Gly Asn Ala Thr Ala260 265 270atc ttc ttc ctg cct gat gag ggg aaa cta cag cac ctg gaa aat gaa 1102Ile Phe Phe Leu Pro Asp Glu Gly Lys Leu Gln His Leu Glu Asn Glu275 280 285 290ctc acc cac gat atc atc acc aag ttc ctg gaa aat gaa gac aga agg 1150Leu Thr His Asp Ile Ile Thr Lys Phe Leu Glu Asn Glu Asp Arg Arg295 300 305tct gcc agc tta cat tta ccc aaa ctg tcc att act gga acc tat gat 1198Ser Ala Ser Leu His Leu Pro Lys Leu Ser Ile Thr Gly Thr Tyr Asp310 315 320ctg aag agc gtc ctg ggt caa ctg ggc atc act aag gtc ttc agc aat 1246Leu Lys Ser Val Leu Gly Gln Leu Gly Ile Thr Lys Val Phe Ser Asn325 330 335ggg gct gac ctc tcc ggg gtc aca gag gag gca ccc ctg aag ctc tcc 1294Gly Ala Asp Leu Ser Gly Val Thr Glu Glu Ala Pro Leu Lys Leu Ser340 345 350aag gcc gtg cat aag gct gtg ctg acc atc gac gag aaa ggg act gaa 1342Lys Ala Val His Lys Ala Val Leu Thr Ile Asp Glu Lys Gly Thr Glu355 360 365 370gct gct ggg gcc atg ttt tta gag gcc ata ccc atg tct atc ccc ccc 1390
Ala Ala Gly Ala Met Phe Leu Glu Ala Ile Pro Met Ser Ile Pro Pro375 380 385gag gtc aag ttc aac aaa ccc ttt gtc ttc tta atg att gac caa aat 1438Glu Val Lys Phe Asn Lys Pro Phe Val Phe Leu Met Ile Asp Gln Asn390 395 400acc aag tct ccc ctc ttc atg gga aaa gtg gtg aat ccc acc caa aaa 1486Thr Lys Ser Pro Leu Phe Met Gly Lys Val Val Asn Pro Thr Gln Lys405 410 415taa ctgcctctcg ctcctcaacc cctcccctcc atccctggcc ccctccctgg 1539*atgacattaa agaagggttg agctggaaaa aaaaaaaaaa aaaaa1584<210>2<211>1413<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(227)...(1285)<400>2ccggcctctt ggtactgctg accccagcca ggctacaggg atcgattgga gctgtccttg 60gggctgtaat tggccccagc tgagcagggc aaacactgag gtcaactaca agccacaggc 120cccttcccca gcctcagttc acagctgccc tgttgcaggg aggcggtggc ccttctgttg 180ctagaccgag cctgtgggat ataccaaggc agaggagccc atagcc atg agg agc235Met Arg Ser1ctc ggg gcc ctg ctc ttg ctg ctg agc gcc tgc ctg gcg gtg agc gct 283Leu Gly Ala Leu Leu Leu Leu Leu Ser Ala Cys Leu Ala Val Ser Ala5 10 15ggc cct gtg cca acg ccg ccc gac aac atc caa gtg cag gaa aac ttc 331Gly Pro Val Pro Thr Pro Pro Asp Asn Ile Gln Val Gln Glu Asn Phe20 25 30 35aat atc tct cgg atc tat ggg aag tgg tac aac ctg gcc atc ggt tcc 379Asn Ile Ser Arg Ile Tyr Gly Lys Trp Tyr Asn Leu Ala Ile Gly Ser
40 45 50acc tgc ccc tgg ctg aag aag atc atg gac agg atg aca gtg agc acg 427Thr Cys Pro Trp Leu Lys Lys Ile Met Asp Arg Met Thr Val Ser Thr55 60 65ctg gtg ctg gga gag ggc gct aca gag gcg gag atc agc atg acc agc 475Leu Val Leu Gly Glu Gly Ala Thr Glu Ala Glu Ile Ser Met Thr Ser70 75 80act cgt tgg cgg aaa ggt gtc tgt gag gag acg tct gga gct tat gag 523Thr Arg Trp Arg Lys Gly Val Cys Glu Glu Thr Ser Gly Ala Tyr Glu85 90 95aaa aca gat act gat ggg aag ttt ctc tat cac aaa tcc aaa tgg aac 571Lys Thr Asp Thr Asp Gly Lys Phe Leu Tyr His Lys Ser Lys Trp Asn100 105 110 115ata acc atg gag tcc tat gtg gtc cac acc aac tat gat gag tat gcc 619Ile Thr Met Glu Ser Tyr Val Val His Thr Asn Tyr Asp Glu Tyr Ala120 125 130att ttc ctg acc aag aaa ttc agc cgc cat cat gga ccc acc att act 667Ile Phe Leu Thr Lys Lys Phe Ser Arg His His Gly Pro Thr Ile Thr135 140 145gcc aag ctc tac ggg cgg gcg ccg cag ctg agg gaa act ctc ctg cag 715Ala Lys Leu Tyr Gly Arg Ala Pro Gln Leu Arg Glu Thr Leu Leu Gln150 155 160gac ttc aga gtg gtt gcc cag ggt gtg ggc atc cct gag gac tcc atc 763Asp Phe Arg Val Val Ala Gln Gly Val Gly Ile Pro Glu Asp Ser Ile165 170 175ttc acc atg gct gac cga ggt gaa tgt gtc cct ggg gag cag gaa cca 811Phe Thr Met Ala Asp Arg Gly Glu Cys Val Pro Gly Glu Gln Glu Pro180 185 190 195gag ccc atc tta atc ccg aga gtc cgg agg gct gtg cta ccc caa gaa 859Glu Pro Ile Leu Ile Pro Arg Val Arg Arg Ala Val Leu Pro Gln Glu200 205 210gag gaa gga tca ggg ggt ggg caa ctg gta act gaa gtc acc aag aaa 907Glu Glu Gly Ser Gly Gly Gly Gln Leu Val Thr Glu Val Thr Lys Lys
215 220 225gaa gat tcc tgc cag ctg ggc tac tcg gcc ggt ccc tgc atg gga atg 955Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala Gly Pro Cys Met Gly Met230 235 240acc agc agg tat ttc tat aat ggt aca tcc atg gcc tgt gag act ttc 1003Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser Met Ala Cys Glu Thr Phe245 250 255cag tac ggc ggc tgc atg ggc aac ggt aac aac ttc gtc aca gaa aag 1051Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn Asn Phe Val Thr Glu Lys260 265 270275gag tgt ctg cag acc tgc cga act gtg gcg gcc tgc aat ctc ccc ata 1099Glu Cys Leu Gln Thr Cys Arg Thr Val Ala Ala Cys Asn Leu Pro Ile280 285 290gtc cgg ggc ccc tgc cga gcc ttc atc cag ctc tgg gca ttt gat gct 1147Val Arg Gly Pro Cys Arg Ala Phe Ile Gln Leu Trp Ala Phe Asp Ala295 300 305gtc aag ggg aag tgc gtc ctc ttc ccc tac ggg ggc tgc cag ggc aac 1195Val Lys Gly Lys Cys Val Leu Phe Pro Tyr Gly Gly Cys Gln Gly Asn310 315 320ggg aac aag ttc tac tca gag aag gag tgc aga gag tac tgc ggt gtc 1243Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr Cys Gly Val325 330 335cct ggt gat ggt gat gag gag ctg ctg cgc ttc tcc aac tga 1285Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg Phe Ser Asn *340 345 350caactggccg gtctgcaagt cagaggatgg ccagtgtctg tcccggggtc ctgtggcagg 1345cagcgccaag caacctgggt ccaaataaaa actaaattgt aaactcctga aaaaaaaaaa 1405aaaaaaaa 1413<210>3<211>2856<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(162)...(1358)<400>3actttccctt tcgaattcct cggtatatct tggggactgg aggacctgtc tggttattat 60acagacgcat aactggaggt gggatccaca cagctcagaa cagctggatc ttgctcagtc 120tctgccaggg gaagattcct tggaggaggc cctgcagcga c atg gag gga gct gct 176Met Glu Gly Ala Ala1 5ttg ctg aga gtc tct gtc ctc tgc atc tgg atg agt gca ctt ttc ctt 224Leu Leu Arg Val Ser Val Leu Cys Ile Trp Met Ser Ala Leu Phe Leu10 15 20ggt gtg gga gtg agg gca gag gaa gct gga gcg agg gtg caa caa aac 272Gly Val Gly Val Arg Ala Glu Glu Ala Gly Ala Arg Val Gln Gln Asn25 30 35gtt cca agt ggg aca gat act gga gat cct caa agt aag ccc ctc ggt 320Val Pro Ser Gly Thr Asp Thr Gly Asp Pro Gln Ser Lys Pro Leu Gly40 45 50gac tgg gct gct ggc acc atg gac cca gag agc agt atc ttt att gag 368Asp Trp Ala Ala Gly Thr Met Asp Pro Glu Ser Ser Ile Phe lle Glu55 60 65gat gcc att aag tat ttc aag gaa aaa gtg agc aca cag aat ctg cta 416Asp Ala Ile Lys Tyr Phe Lys Glu Lys Val Ser Thr Gln Asn Leu Leu70 75 80 85ctc ctg ctg act gat aat gag gcc tgg aac gga ttc gtg gct gct gct 464Leu Leu Leu Thr Asp Asn Glu Ala Trp Asn Gly Phe Val Ala Ala Ala90 95 100gaa ctg ccc agg aat gag gca gat gag ctc cgt aaa gct ctg gac aac 512Glu Leu Pro Arg Asn Glu Ala Asp Glu Leu Arg Lys Ala Leu Asp Asn105 110 115ctt gca aga caa atg atc atg aaa gac aaa aac tgg cac gat aaa ggc 560Leu Ala Arg Gln Met Ile Met Lys Asp Lys Asn Trp His Asp Lys Gly120 125 130cag cag tac aga aac tgg ttt ctg aaa gag ttt cct cgg ttg aaa agt 608Gln Gln Tyr Arg Asn Trp Phe Leu Lys Glu Phe Pro Arg Leu Lys Ser
135 140 145gag ctt gag gat aac ata aga agg ctc cgt gcc ctt gca gat ggg gtt 656Glu Leu Glu Asp Asn Ile Arg Arg Leu Arg Ala Leu Ala Asp Gly Val150 155 160 165cag aag gtc cac aaa ggc acc acc atc gcc aat gtg gtg tct ggc tct 704Gln Lys Val His Lys Gly Thr Thr Ile Ala Asn Val Val Ser Gly Ser170 175 180ctc agc att tcc tct ggc atc ctg acc ctc gtc ggc atg ggt ctg gca 752Leu Ser Ile Ser Ser Gly Ile Leu Thr Leu Val Gly Met Gly Leu Ala185 190 195ccc ttc aca gag gga ggc agc ctt gta ctc ttg gaa cct ggg atg gag 800Pro Phe Thr Glu Gly Gly Ser Leu Val Leu Leu Glu Pro Gly Met Glu200 205 210ttg gga atc aca gcc gct ttg acc ggg att acc agc agt acc atg gac 848Leu Gly Ile Thr Ala Ala Leu Thr Gly Ile Thr Ser Ser Thr Met Asp215 220 225tac gga aag aag tgg tgg aca caa gcc caa gcc cac gac ctg gtc atc 896Tyr Gly Lys Lys Trp Trp Thr Gln Ala Gln Ala His Asp Leu Val Ile230 235 240 245aaa agc ctt gac aaa ttg aag gag gtg agg gag ttt ttg ggt gag aac 944Lys Ser Leu Asp Lys Leu Lys Glu Val Arg Glu Phe Leu Gly Glu Asn250 255 260ata tcc aac ttt ctt tcc tta gct ggc aat act tac caa ctc aca cga 992Ile Ser Asn Phe Leu Ser Leu Ala Gly Asn Thr Tyr Gln Leu Thr Arg265 270 275ggc att ggg aag gac atc cgt gcc ctc aga cga gcc aga gcc aat ctt 1040Gly Ile Gly Lys Asp Ile Arg Ala Leu Arg Arg Ala Arg Ala Asn Leu280 285 290cag tca gta ccg cat gcc tca gcc tca cgc ccc cgg gtc act gag cca 1088Gln Ser Val Pro His Ala Ser Ala Ser Arg Pro Arg Val Thr Glu Pro295 300 305atc tca gct gaa agc ggt gaa cag gtg gag agg gtt aat gaa ccc agc 1136Ile Ser Ala Glu Ser Gly Glu Gln Val Glu Arg Val Asn Glu Pro Ser
310 315 320 325atc ctg gaa atg agc aga gga gtc aag ctc acg gat gtg gcc cct gta 1184Ile Leu Glu Met Ser Arg Gly Val Lys Leu Thr Asp Val Ala Pro Val330 335 340agc ttc ttt ctt gtg ctg gat gta gtc tac ctc gtg tac gaa tca aag 1232Ser Phe Phe Leu Val Leu Asp Val Val Tyr Leu Val Tyr Glu Ser Lys345 350 355cac tta cat gag ggg gca aag tca gag aca gct gag gag ctg aag aag 1280His Leu His Glu Gly Ala Lys Ser Glu Thr Ala Glu Glu Leu Lys Lys360 365 370gtg gct cag gag ctg gag gag aag cta aac att ctc aac aat aat tat 1328Val Ala Gln Glu Leu Glu Glu Lys Leu Asn Ile Leu Asn Asn Asn Tyr375 380 385aag att ctg cag gcg gac caa gaa ctg tga ccacagggca gggcagccac 1378Lys Ile Leu Gln Ala Asp Gln Glu Leu *390 395caggagagat atgcctggca ggggccagga caaaatgcaa actttttttt ttttctgaga 1438cagagtcttg ctctgtcgcc aagttggagt gcaatggtgc gatctcagct cactgcaagc 1498tctgcctccc gtgttcaagc gattctcctg ccttggcctc ccaagtagct gggactacag 1558gcgcctacca ccatgcccag ctaatttttg tatttttaat agagatgggg tttcaccatg 1618ttggccagga tggtctcgat ctcctgacct cttgatctgc ccaccttggc ctcccaaagt 1678gctgggatta caggcgtgag ccatcgcttt tgacccaaat gcaaacattt tattaggggg 1738ataaagaggg tgaggtaaag tttatggaac tgagtgttag ggactttggc atttc1catag1798ctgagcacag caggggaggg gttaatgcag atggcagtgc agcaaggaga aggcaggaac 1858attggagcct gcaataaggg aaaaatggga actggagagt gtggggaatg ggaagaagca 1918gtttacttta gactaaagaa tatattgggg ggccgggtgt agtggctcat gcctgtaatc 1978cgagcacttt gggaggccaa ggcgggcgga tcacgaggtc aggagatcga gaccatcctg 2038gctaacacag tgaaaccccg tctctactaa aaatacaaaa aattagccgg gcatggtggc 2098gggcgcctgt agttccagct aactgggcgg ctgaggcagg agaatggcgt gaacctggga 2158ggtggagctt gcagtgagcc gagatatcgc cactgcactc cagcctgggt gacagagcga 2218gactccatct caaaaaaaaa aaaaaaaaga atatattgac ggaagaatag agaggaggct 2278tgaaggaacc agcaatgaga aggccaggaa aagaaagagc tgaaaatgga gaaagcccaa 2338gagttagaac agttggatac aggagaagaa acagcggctc cactacagac ccagccccag 2398gttcaatgtc ctccgaagaa tgaagtcttt ccctggtgat ggtcccctgc cctgtctttc 2458cagcatccac tctcccttgt cctcctgggg gcatatctca gtcaggcagc ggcttcctga 2518tgatggtcat tggggtggtt gtcatgtgat gggtcccctc caggttacta aagggtgcat 2578gtcccctgct tgaacactga agggcaggtg gtgggccatg gccatggtcc ccagctgagg 2638agcaggtgtc cctgagaacc caaacttccc agagagtatg tgagaaccaa ccaatgaaaa 2698
cagtcccatc gctcttaccc ggtaagtaaa cagtcagaaa attagcatga aagcagttta 2758gcattgggag gaagctcaga tctctagagc tgtcttgtcg ccgcccagga ttgacctgtg 2818tgtaagtccc aataaactca cctactcatc aagctgga 2856<210>4<211>576<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(46)...(390)<400>4aaacactctg tgtggctcct cggctttggg acagagtgca agacg atg act tgc aaa 57Met Thr Cys Lys1atg tcg cag ctg gaa cgc aac ata gag acc atc atc aac acc ttc cac 105Met Ser Gln Leu Glu Arg Asn Ile Glu Thr Ile Ile Asn Thr Phe His5 10 15 20caa tac tct gtg aag ctg ggg cac cca gac acc ctg aac cag ggg gaa 153Gln Tyr Ser Val Lys Leu Gly His Pro Asp Thr Leu Asn Gln Gly Glu25 30 35ttc aaa gag ctg gtg cga aaa gat ctg caa aat ttt ctc aag aag gag 201Phe Lys Glu Leu Val Arg Lys Asp Leu Gln Asn Phe Leu Lys Lys Glu40 45 50aat aag aat gaa aag gtc ata gaa cac atc atg gag gac ctg gac aca 249Asn Lys Asn Glu Lys Val Ile Glu His Ile Met Glu Asp Leu Asp Thr55 60 65aat gca gac aag cag ctg agc ttc gag gag ttc atc atg ctg atg gcg 297Asn Ala Asp Lys Gln Leu Ser Phe Glu Glu Phe Ile Met Leu Met Ala70 75 80agg cta acc tgg gcc tcc cac gag aag atg cac gag ggt gac gag ggc 345Arg Leu Thr Trp Ala Ser His Glu Lys Met His Glu Gly Asp Glu Gly85 90 95 100cct ggc cac cac cat aag cca ggc ctc ggg gag ggc acc ccc taa 390Pro Gly His His His Lys Pro Gly Leu Gly Glu Gly Thr Pro *
105 110gaccacagtg gccaagatca cagtggccac ggccatggcc acagtcatgg tggccacggc 450cacaggccac taatcaggag gccaggccac cctgcctcta cccaaccagg gccccggggc 510ctgttatgtc aaactgtctt ggctgtgggg ctaggggctg gggccaaata aagtctcttc 570ctccaa576<210>5<211>1264<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(147)...(932)<400>5gtggtaccca gtcctcaggt gcaaccccct gcgtggtcct ctgtggcagc cttctctcat 60tcagagctgt tttccacaga ggtagtgaaa agaactggat tttcaagttc actttgcaag 120agaaaaagaa aactcagtag aagata atg gca agt cca gac tgg gga tat gat 173Met Ala Ser Pro Asp Trp Gly Tyr Asp1 5gac aaa aat ggt cct gaa caa tgg agc aag ctg tat ccc att gcc aat 221Asp Lys Asn Gly Pro Glu Gln Trp Ser Lys Leu Tyr Pro Ile Ala Asn10 15 20 25gga aat aac caa tcc cct gtt gat att aaa acc agt gaa acc aaa cat 269Gly Asn Asn Gln Ser Pro Val Asp Ile Lys Thr Ser Glu Thr Lys His30 35 40gac acc tct ctg aaa cct att agt gtc tcc tac aac cca gcc aca gcc 317Asp Thr Ser Leu Lys Pro Ile Ser Val Ser Tyr Asn Pro Ala Thr Ala45 50 55aaa gaa att atc aat gtg ggg cat tct ttc cat gta aat ttt gag gac 365Lys Glu Ile Ile Asn Val Gly His Ser Phe His Val Asn Phe Glu Asp60 65 70aac gat aac cga tca gtg ctg aaa ggt ggt cct ttc tct gac agc tac 413Asn Asp Asn Arg Ser Val Leu Lys Gly Gly Pro Phe Ser Asp Ser Tyr75 80 85agg ctc ttt cag ttt cat ttt cac tgg ggc agt aca aat gag cat ggt 461
Arg Leu Phe Gln Phe His Phe His Trp Gly Ser Thr Asn Glu His Gly90 95 100 105tca gaa cat aca gtg gat gga gtc aaa tat tct gcc gag ctt cac gta509Ser Glu His Thr Val Asp Gly Val Lys Tyr Ser Ala Glu Leu His Val110 115 120gct cac tgg aat tct gca aag tac tcc agc ctt gct gaa gct gcc tca557Ala His Trp Asn Ser Ala Lys Tyr Ser Ser Leu Ala Glu Ala Ala Ser125 130 135aag gct gat ggt ttg gca gtt att ggt gtt ttg atg aag gtt ggt gag605Lys Ala Asp Gly Leu Ala Val Ile Gly Val Leu Met Lys Val Gly Glu140 145 150gcc aac cca aag ctg cag aaa gta ctt gat gcc ctc caa gca att aaa653Ala Asn Pro Lys Leu Gln Lys Val Leu Asp Ala Leu Gln Ala Ile Lys155 160 165acc aag ggc aaa cga gcc cca ttc aca aat ttt gac ccc tct act ctc701Thr Lys Gly Lys Arg Ala Pro Phe Thr Asn Phe Asp Pro Ser Thr Leu170 175 180 185ctt cct tca tcc ctg gat ttc tgg acc tac cct ggc tct ctg act cat749Leu Pro Ser Ser Leu Asp Phe Trp Thr Tyr Pro Gly Ser Leu Thr His190 195 200cct cct ctt tat gag agt gta act tgg atc atc tgt aag gag agc atc797Pro Pro Leu Tyr Glu Ser Val Thr Trp Ile Ile Cys Lys Glu Ser Ile205 210 215agt gtc agc tca gag cag ctg gca caa ttc cgc agc ctt cta tca aat845Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser Leu Leu Ser Asn220 225 230gtt gaa ggt gat aac gct gtc ccc atg cag cac aac aac cgc cca acc893Val Glu Gly Asp Asn Ala Val Pro Met Gln His Asn Asn Arg Pro Thr235 240 245caa cct ctg aag ggc aga aca gtg aga gct tca ttt tga tgattctgag 942Gln Pro Leu Lys Gly Arg Thr Val Arg Ala Ser Phe *250 255 260aagaaacttg tccttcctca agaacacagc cctgcttctg acataatcca gttaaaataa 1002
taatttttaa gaaataaatt tatttcaata ttagcaagac agcatgcctt caaatcaatc 1062tgtaaaacta agaaacttaa attttagttc ttactgctta attcaaataa taattagtaa 1122gctagcaaat agtaatctgt aagcataagc ttatcttaaa ttcaagttta gtttgaggaa 1182ttctttaaaa ttacaactaa gtgatttgta tgtctatttt tttcagttta tttgaaccaa 1242taaaataatt ttatctcttt ct 1264<210>6<211>1676<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(48)...(1397)<400>6gaattccgcc gctgaccgag gcgtgcaaag actccagaat tggaggc atg atg aag 56Met Met Lys1act ctg ctg ctg ttt gtg ggg ctg ctg ctg acc tgg gag agt ggg cag 104Thr Leu Leu Leu Phe Val Gly Leu Leu Leu Thr Trp Glu Ser Gly Gln5 10 15gtc ctg ggg gac cag acg gtc tca gac aat gag ctc cag gaa atg tcc 152Val Leu Gly Asp Gln Thr Val Ser Asp Asn Glu Leu Gln Glu Met Ser20 25 30 35aat cag gga agt aag tac gtc aat aag gaa att caa aat gct gtc aac 200Asn Gln Gly Ser Lys Tyr Val Asn Lys Glu Ile Gln Asn Ala Val Asn40 45 50ggg gtg aaa cag ata aag act ctc ata aaa aaa aca aac gaa gag cgc 248Gly Val Lys Gln Ile Lys Thr Leu Ile Glu Lys Thr Asn Glu Glu Arg55 60 65aag aca ctg ctc agc aac cta gaa gaa gcc aag aag aag aaa gag gat 296Lys Thr Leu Leu Ser Asn Leu Glu Glu Ala Lys Lys Lys Lys Glu Asp70 75 80gcc cta aat gag acc agg gaa tca gag aca aag ctg aag gag ctc cca 344Ala Leu Asn Glu Thr Arg Glu Ser Glu Thr Lys Leu Lys Glu Leu Pro85 90 95
gga gtg tgc aat gag acc atg atg gcc ctc tgg gaa gag tgt aag ccc 392Gly Val Cys Asn Glu Thr Met Met Ala Leu Trp Glu Glu Cys Lys Pro100 105 110 115tgc ctg aaa cag acc tgc atg aag ttc tac gca cgc gtc tgc aga agt 440Cys Leu Lys Gln Thr Cys Met Lys Phe Tyr Ala Arg Val Cys Arg Ser120 125 130ggc tca ggc ctg gtt ggc cgc cag ctt gag gag ttc ctg aac cag agc 488Gly Ser Gly Leu Val Gly Arg Gln Leu Glu Glu Phe Leu Asn Gln Ser135 140 145tcg ccc ttc tac ttc tgg atg aat ggt gac cgc atc gac tcc ctg ctg 536Ser Pro Phe Tyr Phe Trp Met Asn Gly Asp Arg Ile Asp Ser Leu Leu150 155 160gag aac gac cgg cag cag acg cac atg ctg gat gtc atg cag gac cac 584Glu Asn Asp Arg Gln Gln Thr His Met Leu Asp Val Met Gln Asp His165 170 175ttc agc cgc gcg tcc agc atc ata gac gag ctc ttc cag gac agg ttc 632Phe Ser Arg Ala Ser Ser Ile Ile Asp Glu Leu Phe Gln Asp Arg Phe180 185 190 195ttc acc cgg gag ccc cag gat acc tac cac tac ctg ccc ttc agc ctg 680Phe Thr Arg Glu Pro Gln Asp Thr Tyr His Tyr Leu Pro Phe Ser Leu200 205 210ccc cac cgg agg cct cac ttc ttc ttt ccc aag tcc cgc atc gtc cgc 728Pro His Arg Arg Pro His Phe Phe Phe Pro Lys Ser Arg Ile Val Arg215 220 225agc ttg atg ccc ttc tct ccg tac gag ccc ctg aac ttc cac gcc atg 776Ser Leu Met Pro Phe Ser Pro Tyr Glu Pro Leu Asn Phe His Ala Met230 235 240ttc cag ccc ttc ctt gag atg ata cac gag gct cag cag gcc atg gac 824Phe Gln Pro Phe Leu Glu Met Ile His Glu Ala Gln Gln Ala Met Asp245 250 255atc cac ttc cac agc ccg gcc ttc cag cac ccg cca aca gaa ttc ata 872Ile His Phe His Ser Pro Ala Phe Gln His Pro Pro Thr Glu Phe Ile260 265 270 275
cga gaa ggc gac gat gac cgg act gtg tgc cgg gag atc cgc cac aac 920Arg Glu Gly Asp Asp Asp Arg Thr Val Cys Arg Glu lle Arg His Asn280 285 290tcc acg ggc tgc ctg cgg atg aag gac cag tgt gac aag tgc cgg gag 968Ser Thr Gly Cys Leu Arg Met Lys Asp Gln Cys Asp Lys Cys Arg Glu295 300 305atc ttg tct gtg gac tgt tcc acc aac aac ccc tcc cag gct aag ctg 1016Ile Leu Ser Val Asp Cys Ser Thr Asn Asn Pro Ser Gln Ala Lys Leu310 315 320cgg cgg gag ctc gac gaa tcc ctc cag gtc gct gag agg ttg acc agg 1064Arg Arg Glu Leu Asp Glu Ser Leu Gln Val Ala Glu Arg Leu Thr Arg325 330 335aaa tac aac gag ctg cta aag tcc tac cag tgg aag atg ctc aac acc 1112Lys Tyr Asn Glu Leu Leu Lys Ser Tyr Gln Trp Lys Met Leu Asn Thr340 345 350 355tcc tcc ttg ctg gag cag ctg aac gag cag ttt aac tgg gtg tcc cgg 1160Ser Ser Leu Leu Glu Gln Leu Asn Glu Gln Phe Asn Trp Val Ser Arg360 365 370ctg gca aac ctc acg caa ggc gaa gac cag tac tat ctg egg gtc acc 1208Leu Ala Asn Leu Thr Gln Gly Glu Asp Gln Tyr Tyr Leu Arg Val Thr375 380 385acg gtg gct tcc cac act tct gac tcg gac gtt cct tcc ggt gtc act 1256Thr Val Ala Ser His Thr Ser Asp Ser Asp Val Pro Ser Gly Val Thr390 395 400gag gtg gtc gtg aag ctc ttt gac tct gat ccc atc act gtg acg gtc 1304Glu Val Val Val Lys Leu Phe Asp Ser Asp Pro Ile Thr Val Thr Val405 410 415cct gta gaa gtc tcc agg aag aac cct aaa ttt atg gag acc gtg gcg 1352Pro Val Glu Val Ser Arg Lys Asn Pro Lys Phe Met Glu Thr Val Ala420 425 430 435gag aaa gcg ctg cag gaa tac cgc aaa aag cac cgg gag gag tga 1397Glu Lys Ala Leu Gln Glu Tyr Arg Lys Lys His Arg Glu Glu *440 445
gatgtggatg ttgcttttgc accttacggg ggcatcttga gtccagctcc ccccaagatg 1457agctgcagcc ccccagagag agctctgcac gtcaccaagt aaccaggccc cagcctccag 1517gcccccaact ccgcccagcc tctccccgct ctggatcctg cactctaaca ctcgactctg 1577ctgctcatgg gaagaacaga attgctcctg catgcaacta attcaataaa actgtcttgt 1637gagctgaaaa aaaaaaaaaa aaaaaaaaaa aaggaattc1676<210>7<211>1059<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(52)...(552)<400>7gctctcgtct tctgcggctc tcggtgccct ctccttttcg tttccggaaa c atg gcc 57Met Ala1tcc ggt gtg gct gtc tct gat ggt gtc atc aag gtg ttc aac gac atg105Ser Gly Val Ala Val Ser Asp Gly Val Ile Lys Val Phe Asn Asp Met5 10 15aag gtg cgt aag tct tca acg cca gag gag gtg aag aag cgc aag aag153Lys Val Arg Lys Ser Ser Thr Pro Glu Glu Val Lys Lys Arg Lys Lys20 25 30gcg gtg ctc ttc tgc ctg agt gag gac aag aag aac atc atc ctg gag201Ala Val Leu Phe Cys Leu Ser Glu Asp Lys Lys Asn Ile Ile Leu Glu35 40 45 50gag ggc aag gag atc ctg gtg ggc gat gtg ggc cag act gtc gac gat249Glu Gly Lys Glu Ile Leu Val Gly Asp Val Gly Gln Thr Val Asp Asp55 60 65ccc tac gcc acc ttt gtc aag atg ctg cca gat aag gac tgc cgc tat297Pro Tyr Ala Thr Phe Val Lys Met Leu Pro Asp Lys Asp Cys Arg Tyr70 75 80gcc ctc tat gat gca acc tat gag acc aag gag agc aag aag gag gat345Ala Leu Tyr Asp Ala Thr Tyr Glu Thr Lys Glu Ser Lys Lys Glu Asp85 90 95
ctg gtg ttt atc ttc tgg gcc ccc gag tct gcg ccc ctt aag agc aaa393Leu Val Phe Ile Phe Trp Ala Pro Glu Ser Ala Pro Leu Lys Ser Lys100 105 110atg att tat gcc agc tcc aag gac gcc atc aag aag aag ctg aca ggg441Met Ile Tyr Ala Ser Ser Lys Asp Ala Ile Lys Lys Lys Leu Thr Gly115 120 125 130atc aag cat gaa ttg caa gca aac tgc tac gag gag gtc aag gac cgc489Ile Lys His Glu Leu Gln Ala Asn Cys Tyr Glu Glu Val Lys Asp Arg135 140 145tgc acc ctg gca gag aag ctg ggg ggc agt gcg gtc atc tcc ctg gag537Cys Thr Leu Ala Glu Lys Leu Gly Gly Ser Ala Val Ile Ser Leu Glu150 155 160ggc aag cct ttg tga gccccttctg gccccctgcc tggagcatct ggcagcccca592Gly Lys Pro Leu *165cacctgccct tgggggttgc aggctgcccc cttcctgcca gaccggaggg gctgggggga 652tcccagcagg gggaggcaat cccttcaccc cagttgccaa acagaccccc caccccctgg 712attttccttc tccctccatc ccttgacggt tctggccttc ccaaactgct tttgatcttt 772tgattcctct tgggctgaag cagaccaagt tccccccagg caccccagtt gtgggggagc 832ctgtattttt tttaacaaca tccccattcc ccacctggtc ctcccccttc ccatgctgcc 892aacttctaac cgcaatagtg actctgtgct tgtctgttta gttctgtgta taaatggaat 952gttgtggaga tgacccctcc ctgtgccggc tggttcctct cccttttccc ctggtcacgg 1012ctactcatgg aagcaggacc agtaagggac cttcgattaa aaaaaaa1059<210>8<211>5067<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(61)...(5052)<400>8ctcctcccca tcctctccct ctgtccctct gtccctctga ccctgcactg tcccagcacc 60atg gga ccc acc tca ggt ccc agc ctg ctg ctc ctg cta cta acc cac 108Met Gly Pro Thr Ser Gly Pro Ser Leu Leu Leu Leu Leu Leu Thr His1 5 10 15
ctc ccc ctg gct ctg ggg agt ccc atg tac tct atc atc acc ccc aac156Leu Pro Leu Ala Leu Gly Ser Pro Met Tyr Ser Ile Ile Thr Pro Asn20 25 30atc ttg cgg ctg gag agc gag gag acc atg gtg ctg gag gcc cac gac204Ile Leu Arg Leu Glu Ser Glu Glu Thr Met Val Leu Glu Ala His Asp35 40 45gcg caa ggg gat gtt cca gtc act gtt act gtc cac gac ttc cca ggc252Ala Gln Gly Asp Val Pro Val Thr ValThr Val His Asp Phe Pro Gly50 55 60aaa aaa cta gtg ctg tcc agt gag aag act gtg ctg acc cct gcc acc300Lys Lys Leu Val Leu Ser Ser Glu Lys Thr Val Leu Thr Pro Ala Thr65 70 75 80aac cac atg ggc aac gtc acc ttc acg atc cca gcc aac agg gag ttc348Asn His Met Gly Asn Val Thr Phe Thr Ile Pro Ala Asn Arg Glu Phe85 90 95aag tca gaa aag ggg cgc aac aag ttc gtg acc gtg cag gcc acc ttc396Lys Ser Glu Lys Gly Arg Asn Lys Phe Val Thr Val Gln Ala Thr Phe100 105 110ggg acc caa gtg gtg gag aag gtg gtg ctg gtc agc ctg cag agc ggg444Gly Thr Gln Val Val Glu Lys Val Val Leu Val Ser Leu Gln Ser Gly115 120 125tac ctc ttc atc cag aca gac aag acc atc tac acc cct ggc tcc aca492Tyr Leu Phe Ile Gln Thr Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr130 135 140gtt ctc tat cgg atc ttc acc gtc aac cac aag ctg cta ccc gtg ggc540Val Leu Tyr Arg lle Phe Thr Val Asn His Lys Leu Leu Pro Val Gly145 150 155 160cgg acg gtc atg gtc aac att gag aac ccg gaa ggc atc ccg gtc aag588Arg Thr Val Met Val Asn Ile Glu Asn Pro Glu Gly Ile Pro Val Lys165 170 175cag gac tcc ttg tct tct cag aac cag ctt ggc gtc ttg ccc ttg tct636Gln Asp Ser Leu Ser Ser Gln Asn Gln Leu Gly Val Leu Pro Leu Ser180 185 190
tgg gac att ccg gaa ctc gtc aac atg ggc cag tgg aag atc cga gcc684Trp Asp Ile Pro Glu Leu Val Asn Met Gly Gln Trp Lys Ile Arg Ala195 200 205tac tat gaa aac tca cca cag cag gtc ttc tcc act gag ttt gag gtg732Tyr Tyr Glu Asn Ser Pro Gln Gln Val Phe Ser Thr Glu Phe Glu Val210 215 220aag gag tac gtg ctg ccc agt ttc gag gtc ata gtg gag cct aca gag780Lys Glu Tyr Val Leu Pro Ser Phe Glu Val Ile Val Glu Pro Thr Glu225 230 235 240aaa ttc tac tac atc tat aac gag aag ggc ctg gag gtc acc atc acc828Lys Phe Tyr Tyr Ile Tyr Asn Glu Lys Gly Leu Glu Val Thr Ile Thr245 250 255gcc agg ttc ctc tac ggg aag aaa gtg gag gga act gcc ttt gtc atc876Ala Arg Phe Leu Tyr Gly Lys Lys Val Glu Gly Thr Ala Phe Val Ile260 265 270ttc ggg atc cag gat ggc gaa cag agg att tcc ctg cct gaa tcc ctc924Phe Gly Ile Gln Asp Gly Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu275 280 285aag cgc att ccg att gag gat ggc tcg ggg gag gtt gtg ctg agc cgg972Lys Arg Ile Pro Ile Glu Asp Gly Ser Gly Glu Val Val Leu Ser Arg290 295 300aag gta ctg ctg gac ggg gtg cag aac ctc cga gca gaa gac ctg gtg1020Lys Val Leu Leu Asp Gly Val Gln Asn Leu Arg Ala Glu Asp Leu Val305 310 315 320ggg aag tct ttg tac gtg tct gcc acc gtc atc ttg cac tca ggc agt1068Gly Lys Ser Leu Tyr Val Ser Ala Thr Val Ile Leu His Ser Gly Ser325 330 335gac atg gtg cag gca gag cgc agc ggg atc ccc atc gtg acc tct ccc1116Asp Met Val Gln Ala Glu Arg Ser Gly Ile Pro Ile Val Thr Ser Pro340 345 350tac cag atc cac ttc acc aag aca ccc aag tac ttc aaa cca gga atg1164Tyr Gln Ile His Phe Thr Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met355 360 365
ccc ttt gac ctc atg gtg ttc gtg acg aac cct gat ggc tct cca gcc 1212Pro Phe Asp Leu Met Val Phe Val Thr Asn Pro Asp Gly Ser Pro Ala370 375 380tac cga gtc ccc gtg gca gtc cag ggc gag gac act gtg cag tct cta 1260Tyr Arg Val Pro Val Ala Val Gln Gly Glu Asp Thr Val Gln Ser Leu385 390 395 400acc cag gga gat ggc gtg gcc aaa ctc agc atc aac aca cac ccc agc 1308Thr Gln Gly Asp Gly Val Ala Lys Leu Ser Ile Asn Thr His Pro Ser405 410 415cag aag ccc ttg agc atc acg gtg cgc acg aag aag cag gag ctc tcg 1356Gln Lys Pro Leu Ser Ile Thr Val Arg Thr Lys Lys Gln Glu Leu Ser420 425 430gag gca gag cag gct acc agg acc atg cag gct ctg ccc tac agc acc 1404Glu Ala Glu Gln Ala Thr Arg Thr Met Gln Ala Leu Pro Tyr Ser Thr435 440 445gtg ggc aac tcc aac aat tac ctg cat ctc tca gtg cta cgt aca gag 1452Val Gly Asn Ser Asn Asn Tyr Leu His Leu Ser Val Leu Arg Thr Glu450 455 460ctc aga ccc ggg gag acc ctc aac gtc aac ttc ctc ctg cga atg gac 1500Leu Arg Pro Gly Glu Thr Leu Asn Val Asn Phe Leu Leu Arg Met Asp465 470 475 480cgc gcc cac gag gcc aag atc cgc tac tac acc tac ctg atc atg aac 1548Arg Ala His Glu Ala Lys Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn485 490 495aag ggc agg ctg ttg aag gcg gga cgc cag gtg cga gag ccc ggc cag 1596Lys Gly Arg Leu Leu Lys Ala Gly Arg Gln Val Arg Glu Pro Gly Gln500 505 510gac ctg gtg gtg ctg ccc ctg tcc atc acc acc gac ttc atc cct tcc 1644Asp Leu Val Val Leu Pro Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser515 520 525ttc cgc ctg gtg gcg tac tac acg ctg atc ggt gcc agc ggc cag agg 1692Phe Arg Leu Val Ala Tyr Tyr Thr Leu Ile Gly Ala Ser Gly Gln Arg530 535 540
gag gtg gtg gcc gac tcc gtg tgg gtg gac gtc aag gac tcc tgc gtg 1740Glu Val Val Ala Asp Ser Val Trp Val Asp Val Lys Asp Ser Cys Val545 550 555 560ggc tcg ctg gtg gta aaa agc ggc cag tca gaa gac cgg cag cct gta 1788Gly Ser Leu Val Val Lys Ser Gly Gln Ser Glu Asp Arg Gln Pro Val565 570 575cct ggg cag cag atg acc ctg aag ata gag ggt gac cac ggg gcc cgg 1836Pro Gly Gln Gln Met Thr Leu Lys Ile Glu Gly Asp His Gly Ala Arg580 585 590gtg gta ctg gtg gcc gtg gac aag ggc gtg ttc gtg ctg aat aag aag 1884Val Val Leu Val Ala Val Asp Lys Gly Val Phe Val Leu Asn Lys Lys595 600 605aac aaa ctg acg cag agt aag atc tgg gac gtg gtg gag aag gca gac 1932Asn Lys Leu Thr Gln Ser Lys Ile Trp Asp Val Val Glu Lys Ala Asp610 615 620atc ggc tgc acc ccg ggc agt ggg aag gat tac gcc ggt gtc ttc tcc 1980Ile Gly Cys Thr Pro Gly Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser625 630 635 640gac gca ggg ctg acc ttc acg agc agc agt ggc cag cag acc gcc cag 2028Asp Ala Gly Leu Thr Phe Thr Ser Ser Ser Gly Gln Gln Thr Ala Gln645 650 655agg gca gaa ctt cag tgc ccg cag cca gcc gcc cgc cga cgc cgt tcc 2076Arg Ala Glu Leu Gln Cys Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser660 665 670gtg cag ctc acg gag aag cga atg gac aaa gtc ggc aag tac ccc aag 2124Val Gln Leu Thr Glu Lys Arg Met Asp Lys Val Gly Lys Tyr Pro Lys675 680 685gag ctg cgc aag tgc tgc gag gac ggc atg cgg gag aac ccc atg agg 2172Glu Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Glu Asn Pro Met Arg690 695 700ttc tcg tgc cag cgc cgg acc cgt ttc atc tcc ctg ggc gag gcg tgc 2220Phe Ser Cys Gln Arg Arg Thr Arg Phe Ile Ser Leu Gly Glu Ala Cys705 710 715 720
aag aag gtc ttc ctg gac tgc tgc aac tac atc aca gag ctg cgg cgg 2268Lys Lys Val Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg725 730 735cag cac gcg cgg gcc agc cac ctg ggc ctg gcc agg agt aac ctg gat 2316Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg Ser Asn Leu Asp740 745 750gag gac atc att gca gaa gag aac atc gtt tcc cga agt gag ttc cca 2364Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg Ser Glu Phe Pro755 760 765gag agc tgg ctg tgg aac gtt gag gac ttg aaa gag cca ccg aaa aat 2412Glu Ser Trp Leu Trp Asn Val Glu Asp Leu Lys Glu Pro Pro Lys Asn770 775 780gga atc tct acg aag ctc atg aat ata ttt ttg aaa gac tcc atc acc 2460Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys Asp Ser Ile Thr785 790 795 800acg tgg gag att ctg gct gtc agc atg tcg gac aag aaa ggg atc tgt 2508Thr Trp Glu Ile Leu Ala Val Ser Met Ser Asp Lys Lys Gly Ile Cys805 810 815gtg gca gac ttc ttc gag gtc aca gta atg cag gac ttc ttc atc gac 2556Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp Phe Phe Ile Asp820 825 830ctg cgg cta ccc tac tct gtt gtt cga aac gag cag gtg gaa atc cga 2604Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile Arg835 840 845gcc gtt ctc tac aat tac cgg cag aac caa gag ctc aag gtg agg gtg 2652Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu Lys Val Arg Val850 855 860gaa cta ctc cac aat cca gcc ttc tgc agc ctg gcc acc acc aag agg 2700Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala Thr Thr Lys Arg865 870 875 880cgt cac cag cag acc gta acc atc ccc ccc aag tcc tcg ttg tcc gtt 2748Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser Ser Leu Ser Val885 890 895
cca tat gtc atc gtg ccg cta aag acc ggc ctg cag gaa gtg gaa gtc 2796Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Leu Gln Glu Val Glu Val900 905 910aag gct gcc gtc tac cat cat ttc atc agt gac ggt gtc agg aag tcc 2844Lys Ala Ala Val Tyr His His Phe Ile Ser Asp Gly Val Arg Lys Ser915 920 925ctg aag gtc gtg ccg gaa gga atc aga atg aac aaa act gtg gct gtt 2892Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys Thr Val Ala Val930 935 940cgc acc ctg gat cca gaa cgc ctg ggc cgt gaa gga gtg cag aaa gag 2940Arg Thr Leu Asp Pro Glu Arg Leu Gly Arg Glu Gly Val Gln Lys Glu945 950 955 960gac atc cca cct gca gac ctc agt gac caa gtc ccg gac acc gag tct 2988Asp Ile Pro Pro Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Glu Ser965 970 975gag acc aga att ctc ctg caa ggg acc cca gtg gcc cag atg aca gag 3036Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Thr Glu980 985990gat gcc gtc gac gcg gaa cgg ctg aag cac ctc att gtg acc ccc tcg 3084Asp Ala Val Asp Ala Glu Arg Leu Lys His Leu Ile Val Thr Pro Ser995 10001005ggc tgc ggg gaa cag aac atg atc ggc atg acg ccc acg gtc atc gct 3132Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro Thr Val Ile Ala101010151020gtg cat tac ctg gat gaa acg gag cag tgg gag aag ttc ggc cta gag 3180Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys Phe Gly Leu Glu1025103010351040aag cgg cag ggg gcc ttg gag ctc atc aag aag ggg tac acc cag cag 3228Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly Tyr Thr Gln Gln104510501055ctg gcc ttc aga caa ccc agc tct gcc ttt gcg gcc ttc gtg aaa cgg 3276Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala Phe Val Lys Arg106010651070
gca ccc agc acc tgg ctg acc gcc tac gtg gtc aag gtc ttc tct ctg 3324Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val Lys Val Phe Ser Leu107510801085gct gtc aac ctc ate gcc atc gac tcc caa gtc ctc tgc ggg gct gtt 3372Ala Val Asn Leu Ile Ala Ile Asp Ser Gln Val Leu Cys Gly Ala Val109010951100aaa tgg ctg atc ctg gag aag cag aag ccc gac ggg gtc ttc cag gag 3420Lys Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly Val Phe Gln Glu1105111011151120gat gcg ccc gtg ata cac caa gaa atg att ggt gga tta cgg aac aac 3468Asp Ala Pro Val Ile His Gln Glu Met Ile Gly Gly Leu Arg Asn Asn112511301135aac gag aaa gac atg gcc ctc acg gcc ttt gtt ctc atc tcg ctg cag 3516Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu Ile Ser Leu Gln114011451150gag gct aaa gat att tgc gag gag cag gtc aac agc ctg cca ggc agc 3564Glu Ala Lys Asp Ile Cys Glu Glu Gln Val Asn Ser Leu Pro Gly Ser11551160 1165atc act aaa gca gga gac ttc ctt gaa gcc aac tac atg aac cta cag 3612Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr Met Asn Leu Gln117011751180aga tcc tac act gtg gcc att gct ggc tat gct ctg gcc cag atg ggc 3660Arg Ser Tyr Thr Val Ala Ile Ala Gly Tyr Ala Leu Ala Gln Met Gly1185119011951200agg ctg aag ggg cct ctt ctt aac aaa ttt ctg acc aca gcc aaa gat 3708Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe Leu Thr Thr Ala Lys Asp120512101215aag aac cgc tgg gag gac cct ggt aag cag ctc tac aac gtg gag gcc 3756Lys Asn Arg Trp Glu Asp Pro Gly Lys Gln Leu Tyr Asn Val Glu Ala1220l2251230aca tcc tat gcc ctc ttg gcc cta ctg cag cta aaa gac ttt gac ttt 3804Thr Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys Asp Phe Asp Phe123512401245
gtg cct ccc gtc gtg cgt tgg ctc aat gaa cag aga tac tac ggt ggt 3852Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg Tyr Tyr Gly Gly125012551260ggc tat ggc tct acc cag gcc acc ttc atg gtg ttc caa gcc ttg gct 3900Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala Leu Ala1265127012751280caa tac caa aag gac gcc cct gac cac cag gaa ctg aac ctt gat gtg 3948Gln Tyr Gln Lys Asp Ala Pro Asp His Gln Glu Leu Asn Leu Asp Val128512901295tcc ctc caa ctg ccc agc cgc agc tcc aag atc acc cac cgt atc cac 3996Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Thr His Arg Ile His130013051310tgg gaa tct gcc agc ctc ctg cga tca gaa gag acc aag gaa aat gag 4044Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu Thr Lys Glu Asn Glu131513201325ggt ttc aca gtc aca gct gaa gga aaa ggc caa ggc acc ttg tcg gtg 4092Gly Phe Thr Val Thr Ala Glu Gly Lys Gly Gln Gly Thr Leu Ser Val133013351340gtg aca atg tac cat gct aag gcc aaa gat caa ctc acc tgt aat aaa 4140Val Thr Met Tyr His Ala Lys Ala Lys Asp Gln Leu Thr Cys Asn Lys1345135013551360ttc gac ctc aag gtc acc ata aaa cca gca ccg gaa aca gaa aag agg 4188Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu Thr Glu Lys Arg136513701375cct cag gat gcc aag aac act atg atc ctt gag atc tgt acc agg tac 4236Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile Cys Thr Arg Tyr138013851390cgg gga gac cag gat gcc act atg tct ata ttg gac ata tcc atg atg 4284Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp Ile Ser Met Met139514001405act ggc ttt gct cca gac aca gat gac ctg aag cag ctg gcc aat ggt 4332Thr Gly Phe Ala Pro Asp Thr Asp Asp Leu Lys Gln Leu Ala Asn Gly141014151420
gtt gac aga tac atc tcc aag tat gag ctg gac aaa gcc ttc tcc gat 4380Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp Lys Ala Phe Ser Asp1425143014351440agg aac acc ctc atc atc tac ctg gac aag gtc tca cac tct gag gat 4428Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys Val Ser His Ser Glu Asp144514501455gac tgt cta gct ttc aaa gtt cac caa tac ttt aat gta gag ctt atc 4476Asp Cys Leu Ala Phe Lys Val His Gln Tyr Phe Asn Val Glu Leu Ile146014651470cag cct gga gca gtc aag gtc tac gcc tat tac aac ctg gag gaa agc 4524Gln Pro Gly Ala Val Lys Val Tyr Ala Tyr Tyr Asn Leu Glu Glu Ser147514801485tgt acc cgg ttc tac cat ccg gaa aag gag gat gga aag ctg aac aag 4572Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly Lys Leu Asn Lys149014951500ctc tgc cgt gat gaa ctg tgc cgc tgt gct gag gag aat tgc ttc ata 4620Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu Asn Cys Phe Ile1505151015151520caa aag tcg gat gac aaa gtc acc ctg gaa gaa cgg ctg gac aag gcc 4668Gln Lys Ser Asp Asp Lys Val Thr Leu Glu Glu Arg Leu Asp Lys Ala152515301535tgt gag cca gga gtg gac tat gtg tac aag acc cga ctg gtc aag gtt 4716Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg Leu Val Lys Val154015451550cag ctg tcc aat gac ttt gac gag tac atc atg gcc att gag cag acc 4764Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met Ala Ile Glu Gln Thr155515601565atc aag tca ggc tcg gat gag gtg cag gtt gga cag cag cgc acg ttc 4812Ile Lys Ser Gly Ser Asp Glu Val Gln Val Gly Gln Gln Arg Thr Phe15701580atc agc ccc atc aag tgc aga gaa gcc ctg aag ctg gag gag aag aaa 4860Ile Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu Glu Glu Lys Lys1585159015951600
cac tac ctc atg tgg ggt ctc tcc tcc gat ttc tgg gga gag aag ccc 4908His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp Gly Glu Lys Pro160516101615aac ctc agc tac atc atc ggg aag gac act tgg gtg gag cac tgg cct 4956Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val Glu His Trp Pro162016251630gag gag gac gaa tgc caa gac gaa gag aac cag aaa caa tgc cag gac 5004Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys Gln Cys Gln Asp163516401645ctc ggc gcc ttc acc gag agc atg gtt gtc ttt ggg tgc ccc aac tga 5052Leu Gly Ala Phe Thr Glu Ser Met Val Val Phe Gly Cys Pro Asn *165016551660ccacaccccc attcc 5067<210>9<211>1040<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(78)...(890)<400>9ggaattcggc acgagattca aagcaacacc accaccactg aagtattttt agttatataa 60gattggaact accaagc atg tgg ctc ctg gtc agt gta att cta atc tca110Met Trp Leu Leu Val Ser Val Ile Leu Ile Ser1 5 10cgg ata tcc tct gtt ggg gga gaa gca atg ttc tgt gat ttt cca aaa 158Arg Ile Ser Ser Val Gly Gly Glu Ala Met Phe Cys Asp Phe Pro Lys15 20 25ata aac cat gga att cta tat gat gaa gaa aaa tat aag cca ttt tcc 206Ile Asn His Gly Ile Leu Tyr Asp Glu Glu Lys Tyr Lys Pro Phe Ser30 35 40caa gtt cct aca ggg gaa gtt ttc tat tac tcc tgt gaa tat aat ttt 254Gln Val Pro Thr Gly Glu Val Phe Tyr Tyr Ser Cys Glu Tyr Asn Phe45 50 55
gtg tct cct tca aaa tcc ttt tgg act cgc ata acg tgc gca gaa gaa302Val Ser Pro Ser Lys Ser Phe Trp Thr Arg Ile Thr Cys Ala Glu Glu60 65 70 75gga tgg tca cca aca cca aag tgt ctc aga ctg tgt ttc ttt cct ttt350Gly Trp Ser Pro Thr Pro Lys Cys Leu Arg Leu Cys Phe Phe Pro Phe80 85 90gtg gaa aat ggt cat tct gaa tct tca gga caa aca cat ctg gaa ggt398Val Glu Asn Gly His Ser Glu Ser Ser Gly Gln Thr His Leu Glu Gly95 100 105gat act gta caa att att tgc aac aca gga tac aga ctt caa aac aat446Asp Thr Val Gln Ile Ile Cys Asn Thr Gly Tyr Arg Leu Gln Asn Asn110 115 120gag aac aac att tca tgt gta gaa cgg ggc tgg tcc act cct ccc aaa494Glu Asn Asn Ile Ser Cys Val Glu Arg Gly Trp Ser Thr Pro Pro Lys125 130 135tgc agg tcc act att tct gca gaa aaa tgt ggg ccc cct cca cct att542Cys Arg Ser Thr Ile Ser Ala Glu Lys Cys Gly Pro Pro Pro Pro Ile140 145 150 155gac aat gga gac att act tca ttc ctg ttg tca gta tat gct cca ggt590Asp Asn Gly Asp Ile Thr Ser Phe Leu Leu Ser Val Tyr Ala Pro Gly160 165 170tca tca gtt gag tac cag tgc cag aac ttg tat caa ctt gag ggt aac638Ser Ser Val Glu Tyr Gln Cys Gln Asn Leu Tyr Gln Leu Glu Gly Asn175 180 185aat caa ata aca tgt aga aac gga caa tgg tca gaa cca cca aaa tgc686Asn Gln Ile Thr Cys Arg Asn Gly Gln Trp Ser Glu Pro Pro Lys Cys190 195 200tta gat cca tgt gta ata tca caa gaa att atg gaa aaa tat aac ata734Leu Asp Pro Cys Val Ile Ser Gln Glu Ile Met Glu Lys Tyr Asn Ile205 210 215aaa tta aag tgg aca aac caa caa aag ctt tat tca aga aca ggt gac782Lys Leu Lys Trp Thr Asn Gln Gln Lys Leu Tyr Ser Arg Thr Gly Asp220 225 230 235
ata gtt gaa ttt gtt tgt aaa tct gga tat cat cca aca aaa tct cat 830Ile Val Glu Phe Val Cys Lys Ser Gly Tyr His Pro Thr Lys Ser His240 245 250tca ttt cga gca atg tgt cag aat ggg aaa ctg gta tat ccc agt tgt 878Ser Phe Arg Ala Met Cys Gln Asn Gly Lys Leu Val Tyr Pro Ser Cys255 260 265gag gaa aaa tag aatcaatggc attactatta gtaaaatgca cacctttttc 930Glu Glu Lys *270tgaatttact attatatttg ttttcaattt catttttcaa gtactgtttt actcattttt 990attcataaat aaagttttgt gttgatttgt gaaaatgcaa ttacaaaaaa 1040<210>10<211>1058<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(11)...(952)<400>10accagaagag atg gag ctg gac aga gct gtg ggg gtc ctg ggc gct gcc49Met Glu Leu Asp Arg Ala Val Gly Val Leu Gly Ala Ala1 5 10acc ctg ctg ctc tct ttc ctg ggc atg gcc tgg gct ctc cag gcg gca 97Thr Leu Leu Leu Ser Phe Leu Gly Met Ala Trp Ala Leu Gln Ala Ala15 20 25gac acc tgt cca gag gtg aag atg gtg ggc ctg gag ggc tet gac aag 145Asp Thr Cys Pro Glu Val Lys Met Val Gly Leu Glu Gly Ser Asp Lys30 35 40 45ctc acc att ctc cga ggc tgt ccg ggg ctg cct ggg gcc cct ggc gac 193Leu Thr Ile Leu Arg Gly Cys Pro Gly Leu Pro Gly Ala Pro Gly Asp50 55 60aag gga gag gca ggc acc aat gga aag aga gga gaa cgt ggc ccc cct 241Lys Gly Glu Ala Gly Thr Asn Gly Lys Arg Gly Glu Arg Gly Pro Pro
65 70 75gga cct cct ggg aag gca gga cca cct ggg ccc aac gga gca cct ggg 289Gly Pro Pro Gly Lys Ala Gly Pro Pro Gly Pro Asn Gly Ala Pro Gly80 85 90gag ccc cag ccg tgc ctg aca ggc ccg cgt acc tgc aag gac ctg cta 337Glu Pro Gln Pro Cys Leu Thr Gly Pro Arg Thr Cys Lys Asp Leu Leu95 100 105gac cga ggg cac ttc ctg agc ggc tgg cac acc atc tac ctg ccc gac 385Asp Arg Gly His Phe Leu Ser Gly Trp His Thr Ile Tyr Leu Pro Asp110 115 120 125tgc cgg ccc ctg act gtg ctc tgt gac atg gac acg gac gga ggg ggc 433Cys Arg Pro Leu Thr Val Leu Cys Asp Met Asp Thr Asp Gly Gly Gly130 135 140tgg acc gtt ttc cag cgg agg gtg gat ggc tct gtg gac ttc tac cgg 481Trp Thr Val Phe Gln Arg Arg Val Asp Gly Ser Val Asp Phe Tyr Arg145 150 155gac tgg gcc acg tac aag cag ggc ttc ggc agt cgg ctg ggg gag ttc 529Asp Trp Ala Thr Tyr Lys Gln Gly Phe Gly Ser Arg Leu Gly Glu Phe160 165 170tgg ctg ggg aat gac aac atc cac gcc ctg acc gcc cag gga acc agc 577Trp Leu Gly Asn Asp Asn Ile His Ala Leu Thr Ala Gln Gly Thr Ser175 180 185gag ctc cgt gta gac ctg gtg gac ttt gag gac aac tac cag ttt gct 625Glu Leu Arg Val Asp Leu Val Asp Phe Glu Asp Asn Tyr Gln Phe Ala190 195 200 205aag tac aga tca ttc aag gtg gcc gac gag gcg gag aag tac aat ctg 673Lys Tyr Arg Ser Phe Lys Val Ala Asp Glu Ala Glu Lys Tyr Asn Leu210 215 220gtc ctg ggg gcc ttc gtg gag ggc agt gcg gga gat tcc ctg acg ttc 721Val Leu Gly Ala Phe Val Glu Gly Ser Ala Gly Asp Ser Leu Thr Phe225 230 235cac aac aac cag tcc ttc tcc acc aaa gac cag gac aat gat ctt aac 769His Asn Asn Gln Ser Phe Ser Thr Lys Asp Gln Asp Asn Asp Leu Asn
240 245 250acc gga aat tgt gct gtg atg ttt cag gga gct tgg tgg tac aaa aac817Thr Gly Asn Cys Ala Val Met Phe Gln Gly Ala Trp Trp Tyr Lys Asn255 260 265tgc cat gtg tca aac ctg aat ggt cgc tac ctc agg ggg act cat ggc865Cys His Val Ser Asn Leu Asn Gly Arg Tyr Leu Arg Gly Thr His Gly270 275 280 285agc ttt gca aat ggc atc aac tgg aag tcg ggg aaa gga tac aat tat913Ser Phe Ala Asn Gly Ile Asn Trp Lys Ser Gly Lys Gly Tyr Asn Tyr290 295 300agc tac aag gtg tca gag atg aag gtg cga cct gcc tag cccaggccgg 962Ser Tyr Lys Val Ser Glu Met Lys Val Arg Pro Ala *305 310cctcagggtc aggacgcctc cacacatagt tggttggggg gtagggtttg ggagcttggc 1022cctacggttt gtaaaagaaa cacatgtcgt gattct1058<210>11<211>1059<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(7)...(906)<400>11agcaag atg gat cta ctg tgg atc ctg ccc tcc ctg tgg ctt ctc ctg48Met Asp Leu Leu Trp Ile Leu Pro Ser Leu Trp Leu Leu Leu1 5 10ctt ggg ggg cct gcc tgc ctg aag acc cag gaa cac ccc agc tgc cca 96Leu Gly Gly Pro Ala Cys Leu Lys Thr Gln Glu His Pro Ser Cys Pro15 20 25 30gga ccc agg gaa ctg gaa gcc agc aaa gtt gtc ctc ctg ccc agt tgt 144Gly Pro Arg Glu Leu Glu Ala Ser Lys Val Val Leu Leu Pro Ser Cys35 40 45ccc gga gct cca gga agt cct ggg gag aag gga gcc cca ggt cct caa 192
Pro Gly Ala Pro Gly Ser Pro Gly Glu Lys Gly Ala Pro Gly Pro Gln50 55 60ggg cca cct gga cca cca ggc aag atg ggc ccc aag ggt gag cca gga 240Gly Pro Pro Gly Pro Pro Gly Lys Met Gly Pro Lys Gly Glu Pro Gly65 70 75gat cca gtg aac ctg ctc cgg tgc cag gaa ggc ccc aga aac tgc cgg 288Asp Pro Val Asn Leu Leu Arg Cys Gln Glu Gly Pro Arg Asn Cys Arg80 85 90gag ctg ttg agc cag ggc gcc acc ttg agc ggc tgg tac cat ctg tgc 336Glu Leu Leu Ser Gln Gly Ala Thr Leu Ser Gly Trp Tyr His Leu Cys95 100 105 110cta cct gag ggc agg gcc ctc cca gtc ttt tgt gac atg gac acc gag 384Leu Pro Glu Gly Arg Ala Leu Pro Val Phe Cys Asp Met Asp Thr Glu115 120 125ggg ggc ggc tgg ctg gtg ttt cag agg cgc cag gat ggt tct gtg gat 432Gly Gly Gly Trp Leu Val Phe Gln Arg Arg Gln Asp Gly Ser Val Asp130 135 140ttc ttc cgc tct tgg tcc tcc tac aga gca ggt ttt ggg aac caa gag 480Phe Phe Arg Ser Trp Ser Ser Tyr Arg Ala Gly Phe Gly Asn Gln Glu145 150 155tct gaa ttc tgg ctg gga aat gag aat ttg cac cag ctt act ctc cag 528Ser Glu Phe Trp Leu Gly Asn Glu Asn Leu His Gln Leu Thr Leu Gln160 165 170ggt aac tgg gag ctg cgg gta gag ctg gaa gac ttt aat ggt aac cgt 576Gly Asn Trp Glu Leu Arg Val Glu Leu Glu Asp Phe Asn Gly Asn Arg175 180 185 190act ttc gcc cac tat gcg acc ttc cgc ctc ctc ggt gag gta gac cac 624Thr Phe Ala His Tyr Ala Thr Phe Arg Leu Leu Gly Glu Val Asp His195 200 205tac cag ctg gca ctg ggc aag ttc tca gag ggc act gca ggg gat tcc 672Tyr Gln Leu Ala Leu Gly Lys Phe Ser Glu Gly Thr Ala Gly Asp Ser210 215 220ctg agc ctc cac agt ggg agg ccc ttt acc acc tat gac gct gac cac 720
Leu Ser Leu His Ser Gly Arg Pro Phe Thr Thr Tyr Asp Ala Asp His225 230 235gat tca agc aac agc aac tgt gca gtg att gtc cac ggt gcc tgg tgg768Asp Ser Ser Asn Ser Asn Cys Ala Val Ile Val His Gly Ala Trp Trp240 245 250tat gca tcc tgt tac cga tca aat ctc aat ggt cgc tat gca gtg tct816Tyr Ala Ser Cys Tyr Arg Ser Asn Leu Asn Gly Arg Tyr Ala Val Ser255 260 265 270gag gct gcc gcc cac aaa tat ggc att gac tgg gcc tca ggc cgt ggt864Glu Ala Ala Ala His Lys Tyr Gly Ile Asp Trp Ala Ser Gly Arg Gly275 280 285gtg ggc cac ccc tac cgc agg gtt cgg atg atg ctt cga tag906Val Gly His Pro Tyr Arg Arg Val Arg Met Met Leu Arg *290 295ggcactctgg cagccagtgc ccttatctct cctgtacagc ttccggatcg tcagccacct 966tgcctttgcc aaccacctct gcttgcctgt ccacatttaa aaataaaatc attttagccc 1026tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 1059<210>12<211>2705<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(48)...(2396)<400>12acccgaggcc gcggctgccg actgggtccc ctgccgctgt cgccacc atg gct ccg 56Met Ala Pro1cac cgc ccc gcg ccc gcg ctg ctt tgc gcg ctg tcc ctg gcg ctg tgc 104His Arg Pro Ala Pro Ala Leu Leu Cys Ala Leu Ser Leu Ala Leu Cys5 10 15gcg ctg tcg ctg ccc gtc cgc gcg gcc act gcg tcg cgg ggg gcg tcc 152Ala Leu Ser Leu Pro Val Arg Ala Ala Thr Ala Ser Arg Gly Ala Ser20 25 30 35
cag gcg ggg gcg ccc cag ggg cgg gtg ccc gag gcg cgg ccc aac agc 200Gln Ala Gly Ala Pro Gln Gly Arg Val Pro Glu Ala Arg Pro Asn Ser40 45 50atg gtg gtg gaa cac ccc gag ttc ctc aag gca ggg aag gag cct ggc 248Met Val Val Glu His Pro Glu Phe Leu Lys Ala Gly Lys Glu Pro Gly55 60 65ctg cag atc tgg cgt gtg gag aag ttc gat ctg gtg ccc gtg ccc acc 296Leu Gln Ile Trp Arg Val Glu Lys Phe Asp Leu Val Pro Val Pro Thr70 75 80aac ctt tat gga gac ttc ttc acg ggc gac gcc tac gtc atc ctg aag 344Asn Leu Tyr Gly Asp Phe Phe Thr Gly Asp Ala Tyr Val Ile Leu Lys85 90 95aca gtg cag ctg agg aac gga aat ctg cag tat gac ctc cac tac tgg 392Thr Val Gln Leu Arg Asn Gly Asn Leu Gln Tyr Asp Leu His Tyr Trp100 105 110 115ctg ggc aat gag tgc agc cag gat gag agc ggg gcg gcc gcc atc ttt 440Leu Gly Asn Glu Cys Ser Gln Asp Glu Ser Gly Ala Ala Ala Ile Phe120 125 130acc gtg cag ctg gat gac tac ctg aac ggc cgg gcc gtg cag cac cgt 488Thr Val Gln Leu Asp Asp Tyr Leu Asn Gly Arg Ala Val Gln His Arg135 140 145gag gtc cag ggc ttc gag tcg gcc acc ttc cta ggc tacttc aag tct536Glu Val Gln Gly Phe Glu Ser Ala Thr Phe Leu Gly Tyr Phe Lys Ser150 155 160ggc ctg aag tac aag aaa gga ggt gtg gca tca gga ttc aag cac gtg 584Gly Leu Lys Tyr Lys Lys Gly Gly Val Ala Ser Gly Phe Lys His Val165 170 175gta ccc aac gag gtg gtg gtg cag aga ctc ttc cag gtc aaa ggg cgg 632Val Pro Asn Glu Val Val Val Gln Arg Leu Phe Gln Val Lys Gly Arg180 185 190 195cgt gtg gtc cgt gcc acc gag gta cct gtg tcc tgg gag agc ttc aac 680Arg Val Val Arg Ala Thr Glu Val Pro Val Ser Trp Glu Ser Phe Asn200 205 210
aat ggc gac tgc ttc atc ctg gac ctg ggc aac aac atc cac cag tgg 728Asn Gly Asp Cys Phe Ile Leu Asp Leu Gly Asn Asn Ile His Gln Trp215 220 225tgt ggt tcc aac agc aat cgg tat gaa aga ctg aag gcc aca cag gtg 776Cys Gly Ser Asn Ser Asn Arg Tyr Glu Arg Leu Lys Ala Thr Gln Val230 235 240tcc aag ggc atc cgg gac aac gag cgg agt ggc cgg gcc cga gtg cac 824Ser Lys Gly Ile Arg Asp Asn Glu Arg Ser Gly Arg Ala Arg Val His245 250 255gtg tct gag gag ggc act gag ccc gag gcg atg ctc cag gtg ctg ggc 872Val Ser Glu Glu Gly Thr Glu Pro Glu Ala Met Leu Gln Val Leu Gly260 265 270 275ccc aag ccg gct ctg cct gca ggt acc gag gac acc gcc aag gag gat 920Pro Lys Pro Ala Leu Pro Ala Gly Thr Glu Asp Thr Ala Lys Glu Asp280 285 290gcg gcc aac cgc aag ctg gcc aag ctc tac aag gtc tcc aat ggt gca 968Ala Ala Asn Arg Lys Leu Ala Lys Leu Tyr Lys Val Ser Asn Gly Ala295 300 305ggg acc atg tcc gtc tcc ctc gtg gct gat gag aac ccc ttc gcc cag 1016Gly Thr Met Ser Val Ser Leu Val Ala Asp Glu Asn Pro Phe Ala Gln310 315 320ggg gcc ctg aag tca gag gac tgc ttc atc ctg gac cac ggc aaa gat 1064Gly Ala Leu Lys Ser Glu Asp Cys Phe Ile Leu Asp His Gly Lys Asp325 330 335ggg aaa atc ttt gtc tgg aaa ggc aag cag gca aac acg gag gag agg 1112Gly Lys Ile Phe Val Trp Lys Gly Lys Gln Ala Asn Thr Glu Glu Arg340 345 350 355aag gct gcc ctc aaa aca gcc tct gac ttc atc acc aag atg gac tac 1160Lys Ala Ala Leu Lys Thr Ala Ser Asp Phe Ile Thr Lys Met Asp Tyr360 365 370ccc aag cag act cag gtc tcg gtc ctt cct gag ggc ggt gag acc cca 1208Pro Lys Gln Thr Gln Val Ser Val Leu Pro Glu Gly Gly Glu Thr Pro375 380 385
ctg ttc aag cag ttc ttc aag aac tgg cgg gac cca gac cag aca gat 1256Leu Phe Lys Gln Phe Phe Lys Asn Trp Arg Asp Pro Asp Gln Thr Asp390 395 400ggc ctg ggc ttg tcc tac ctt tcc agc cat atc gcc aac gtg gag cgg 1304Gly Leu Gly Leu Ser Tyr Leu Ser Ser His Ile Ala Asn Val Glu Arg405 410 415gtg ccc ttc gac gcc gcc acc ctg cac acc tcc act gcc atg gcc gcc 1352Val Pro Phe Asp Ala Ala Thr Leu His Thr Ser Thr Ala Met Ala Ala420 425 430 435cag cac ggc atg gat gac gat ggc aca ggc cag aaa cag atc tgg aga 1400Gln His Gly Met Asp Asp Asp Gly Thr Gly Gln Lys Gln Ile Trp Arg440 445 450atc gaa ggt tcc aac aag gtg ccc gtg gac cct gcc aca tat gga cag 1448Ile Glu Gly Ser Asn Lys Val Pro Val Asp Pro Ala Thr Tyr Gly Gln455 460 465ttc tat gga ggc gac agc tac atc att ctg tac aac tac cgc cat ggt 1496Phe Tyr Gly Gly Asp Ser Tyr Ile Ile Leu Tyr Asn Tyr Arg His Gly470 475 480ggc cgc cag ggg cag ata atc tat aac tgg cag ggt gcc cag tct acc 1544Gly Arg Gln Gly Gln Ile Ile Tyr Asn Trp Gln Gly Ala Gln Ser Thr485 490 495cag gat gag gtc gct gca tct gcc atc ctg act gct cag ctg gat gag 1592Gln Asp Glu Val Ala Ala Ser Ala Ile Leu Thr Ala Gln Leu Asp Glu500 505 510 515gag ctg gga ggt acc cct gtc cag agc cgt gtg gtc caa ggc aag gag 1640Glu Leu Gly Gly Thr Pro Val Gln Ser Arg Val Val Gln Gly Lys Glu520 525 530ccc gcc cac ctc atg agc ctg ttt ggt ggg aag ccc atg atc atc tac 1688Pro Ala His Leu Met Ser Leu Phe Gly Gly Lys Pro Met Ile Ile Tyr535 540 545aag ggc ggc acc tcc cgc gag ggc ggg cag aca gcc cct gcc agc acc 1736Lys Gly Gly Thr Ser Arg Glu Gly Gly Gln Thr Ala Pro Ala Ser Thr550 555 560
cgc ctc ttc cag gtc cgc gcc aac agc gct gga gcc acc cgg gct gtt 1784Arg Leu Phe Gln Val Arg Ala Asn Ser Ala Gly Ala Thr Arg Ala Val565 570 575gag gta ttg cct aag gct ggt gca ctg aac tcc aac gat gcc ttt gtt 1832Glu Val Leu Pro Lys Ala Gly Ala Leu Asn Ser Asn Asp Ala Phe Val580 585 590 595ctg aaa acc ccc tca gcc gcc tac ctg tgg gtg ggt aca gga gcc agc 1880Leu Lys Thr Pro Ser Ala Ala Tyr Leu Trp Val Gly Thr Gly Ala Ser600 605 610gag gca gag aag acg ggg gcc cag gag ctg ctc agg gtg ctg cgg gcc 1928Glu Ala Glu Lys Thr Gly Ala Gln Glu Leu Leu Arg Val Leu Arg Ala615 620 625caa cct gtg cag gtg gca gaa ggc agc gag cca gat ggc ttc tgg gag 1976Gln Pro Val Gln Val Ala Glu Gly Ser Glu Pro Asp Gly Phe Trp Glu630 635 640gcc ctg ggc ggg aag gct gcc tac cgc aca tcc cca cgg ctg aag gac 2024Ala Leu Gly Gly Lys Ala Ala Tyr Arg Thr Ser Pro Arg Leu Lys Asp645 650 655aag aag atg gat gcc cat cct cct cgc ctc ttt gcc tgc tcc aac aag 2072Lys Lys Met Asp Ala His Pro Pro Arg Leu Phe Ala Cys Ser Asn Lys660 665 670 675att gga cgt ttt gtg atc gaa gag gtt cct ggt gag ctc atg cag gaa 2120Ile Gly Arg Phe Val Ile Glu Glu Val Pro Gly Glu Leu Met Gln Glu680 685 690gac ctg gca acg gat gac gtc atg ctt ctg gac acc tgg gac cag gtc 2168Asp Leu Ala Thr Asp Asp Val Met Leu Leu Asp Thr Trp Asp Gln Val695 700 705ttt gtc tgg gtt gga aag gat tct caa gaa gaa gaa aag aca gaa gcc 2210Phe Val Trp Val aly Lys Asp Ser Gln Glu Glu Glu Lys Thr Glu Ala710 715 720ttg act tct gct aag cgg tac atc gag acg gac cca gcc aat cgg gat 2264Leu Thr Ser Ala Lys Arg Tyr Ile Glu Thr Asp Pro Ala Asn Arg Asp725 730 735
cgg cgg acg ccc atc acc gtg gtg aag caa ggc ttt gag cct ccc tcc 2312Arg Arg Thr Pro Ile Thr Val Val Lys Gln Gly Phe Glu Pro Pro Ser740 745 750 755ttt gtg ggc tgg ttc ctt ggc tgg gat gat gat tac tgg tct gtg gac 2360Phe Val Gly Trp Phe Leu Gly Trp Asp Asp Asp Tyr Trp Ser Val Asp760 765 770ccc ttg gac agg gcc atg gct gag ctg gct gcc tga ggaggggcag2406Pro Leu Asp Arg Ala Met Ala Glu Leu Ala Ala *775 780ggcccaccca tgtcaccggt cagtgccttt tggaactgtc cttccctcaa agaggcctta 2466gagcgagcag agcagctctg ctatgagtgt gtgtgtgtgt gtgtgttgtt tctttttttt 2526ttttttacag tatccaaaaa tagccctgca aaaattcaga gtccttgcaa aattgtctaa 2586aatgtcagtg tttgggaaat taaatccaat aaaaacattt tgaagtgtga aaaaaaaaaa 2646aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa 2705<210>13<211>1412<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(27)...(1247)<400>13ctcttccaga ggcaagacca accaag atg agt gcc ttg gga gct gtc att gcc 53Met Ser Ala Leu Gly Ala Val Ile Ala1 5ctc ctg ctc tgg gga cag ctt ttt gca gtg gac tca ggc aat gat gtc 101Leu Leu Leu Trp Gly Gln Leu Phe Ala Val Asp Ser Gly Asn Asp Val10 15 20 25acg gat atc gca gat gac ggc tgc ecg aag ccc ccc gag att gca cat 149Thr Asp Ile Ala Asp Asp Gly Cys Pro Lys Pro Pro Glu Ile Ala His30 35 40ggc tat gtg gag cac tcg gtt cgc tac cag tgt aag aac tac tac aaa 197Gly Tyr Val Glu His Ser Val Arg Tyr Gln Cys Lys Asn Tyr Tyr Lys45 50 55
ctg cgc aca gaa gga gat gga gta tac acc tta aat gat aag aag cag 245Leu Arg Thr Glu Gly Asp Gly Val Tyr Thr Leu Asn Asp Lys Lys Gln60 65 70tgg ata aat aag gct gtt gga gat aaa ctt cct gaa tgt gaa gca gat 293Trp Ile Asn Lys Ala Val Gly Asp Lys Leu Pro Glu Cys Glu Ala Asp75 80 85gac ggc tgc ccg aag ccc ccc gag att gca cat ggc tat gtg gag cac 341Asp Gly Cys Pro Lys Pro Pro Glu Ile Ala His Gly Tyr Val Glu His90 95 100 105tcg gtt cgc tac cag tgt aag aac tac tac aaa ctg cgc aca gaa gga 389Ser ValArg Tyr Gln Cys Lys Asn Tyr Tyr Lys Leu Arg Thr Glu Gly110 115 120gat gga gtg tac acc tta aac aat gag aag cag tgg ata aat aag gct 437Asp Gly Val Tyr Thr Leu Asn Asn Glu Lys Gln Trp Ile Asn Lys Ala125 130 135gtt gga gat aaa ctt cct gaa tgt gaa gca gta tgt ggg aag ccc aag 485Val Gly Asp Lys Leu Pro Glu Cys Glu Ala Val Cys Gly Lys Pro Lys140 145150aat ccg gca aac cca gtg cag cgg atc ctg ggt gga cac ctg gat gcc 533Asn Pro Ala Asn Pro Val Gln Arg Ile Leu Gly GIy His Leu Asp Ala155 160 165aaa ggc agc ttt ccc tgg cag gct aag atg gtt tcc cac cat aat ctc 581Lys Gly Ser Phe Pro Trp Gln Ala Lys Mer Val Ser His His Asn Leu170 175 180 185acc aca ggt gcc acg ctg atc aat gaa caa tgg ctg ctg acc acg gct 629Thr Thr Gly Ala Thr Leu Ile Asn Glu Gln Trp Leu Leu Thr Thr Ala190 195 200aaa aat ctc ttc ctg aac cat tca gaa aat gca aca gcg aaa gac att 677Lys Asn Leu Phe Leu Asn His Ser Glu Asn Ala Thr Ala Lys Asp Ile205 210 215gcc ccc act tta aca ctc tat gtg ggg aaa aag cag ctt gta gag att 725Ala Pro Thr Leu Thr Leu Tyr Val Gly Lys Lys Gln Leu Val Glu Ile220 225 230
gag aag gtt gtt cta cac cct aac tac tcc caa gta gat att ggg ctc 773Glu Lys Val Val Leu His Pro Asn Tyr Ser Gln Val Asp Ile Gly Leu235 240 245atc aaa ctc aaa cag aag gtg tct gtt aat gag aga gtg atg ccc atc 821Ile Lys Leu Lys Gln Lys Val Ser Val Asn Glu Arg Val Met Pro Ile250 255 260 265tgc cta cca tcc aag gat tat gca gaa gta ggg cgt gtg ggt tat gtt 869Cys Leu Pro Ser Lys Asp Tyr Ala Glu Val Gly Arg Val Gly Tyr Val270 275 280tct ggc tgg ggg cga aat gcc aat ttt aaa ttt act gac cat ctg aag 917Ser Gly Trp Gly Arg Asn Ala Asn Phe Lys Phe Thr Asp His Leu Lys285 290 295tat gtc atg ctg cct gtg gct gac caa gac caa tgc ata agg cat tat 965Tyr Val Met Leu Pro Val Ala Asp Gln Asp Gln Cys Ile Arg His Tyr300 305 310gaa ggc agc aca gtc ccc gaa aag aag aca ccg aag agc cct gta ggg 1013Glu Gly Ser Thr Val Pro Glu Lys Lys Thr Pro Lys Ser Pro Val Gly315 320 325gtg cag ccc ata ctg aat gaa cac acc ttc tgt gct ggc atg tct aag 1061Val Gln Pro Ile Leu Asn Glu His Thr Phe Cys Ala Gly Met Ser Lys330 335 340 345tac caa gaa gac acc tgc tat ggc gat gcg ggc agt gcc ttt gcc gtt 1109Tyr Gln Glu Asp Thr Cys Tyr Gly Asp Ala Gly Ser Ala Phe Ala Val350 355 360cac gac ctg gag gag gac acc tgg tat gcg act ggg atc tta agc ttt 1157His Asp Leu Glu Glu Asp Thr Trp Tyr Ala Thr Gly Ile Leu Ser Phe365 370 375gat aag agc tgt gct gtg gct gag tat ggt gtg tat gtg aag gtg act 1205Asp Lys Ser Cys Ala Val Ala Glu Tyr Gly Val Tyr Val Lys Val Thr380 385 390tcc atc cag gac tgg gtt cag aag acc ata gct gag aac taa 1247Ser Ile Gln Asp Trp Val Gln Lys Thr Ile Ala Glu Asn *395 400 405
tgcaaggctg gccggaagcc cttgcctgaa agcaagattt cagcctggaa gagggcaaag 1307tggacgggag tggacaggag tggatgcgat aagatgtggt ttgaagctga tgggtgccag 1367ccctgcattg ctgagtcaat caataaagag ctttcttttg accca 1412<210>14<211>1245<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(31)...(1077)<400>14actgctcttc cagaggcaag accaaccaag atg agt gac ctg gga gct gtc att 54Met Ser Asp Leu Gly Ala Val Ile1 5tcc ctc ctg ctc tgg gga cga cag ctt ttt gca ctg tac tca ggc aat 102Ser Leu Leu Leu Trp Gly Arg Gln Leu Phe Ala Leu Tyr Ser Gly Asn10 15 20gat gtc acg gat att tca gat gac cgc ttc ccg aag ccc cct gag att 150Asp Val Thr Asp Ile Ser Asp Asp Arg Phe Pro Lys Pro Pro Glu Ile25 30 35 40gca aat ggc tat gtg gag cac ttg ttt cgc tac cag tgt aag aac tac 198Ala Asn Gly Tyr Val Glu His Leu Phe Arg Tyr Gln Cys Lys Asn Tyr45 50 55tac aga ctg cgc aca gaa gga gat gga gta tac acc tta aat gat aag 246Tyr Arg Leu Arg Thr Glu Gly Asp Gly Val Tyr Thr Leu Asn Asp Lys60 65 70aag cag tgg ata aat aag gct gtt gga gat aaa ctt cct gaa tgt gaa 294Lys Gln Trp Ile Asn Lys Ala Val Gly Asp Lys Leu Pro Glu Cys Glu75 80 85gca gta tgt ggg aag ccc aag aat ccg gca aac cca gtg cag cgg atc 342Ala Val Cys Gly Lys Pro Lys Asn Pro Ala Asn Pro Val Gln Arg Ile90 95 100ctg ggt gga cac ctg gat gcc aaa ggc agc ttt ccc tgg cag gct aag 390
Leu Gly Gly His Leu Asp Ala Lys Gly Ser Phe Pro Trp Gln Ala Lys105 110 115 120atg gtt tcc cac cat aat ctc acc aca ggg gcc acg ctg atc aat gaa 438Met Val Ser His His Asn Leu Thr Thr Gly Ala Thr Leu Ile Asn Glu125 130 135caa tgg ctg ctg acc acg gct aaa aat ctc ttc ctg aac cat tca gaa 486Gln Trp Leu Leu Thr Thr Ala Lys Asn Leu Phe Leu Asn His Ser Glu140 145 150aat gca aca gcg aaa gac att gcc cct act tta aca ctc tat gtg ggg 534Asn Ala Thr Ala Lys Asp Ile Ala Pro Thr Leu Thr Leu Tyr Val Gly155 160 165aaa aag cag ctt gta gag att gag aag gtg gtt cta cac cct aac tac 582Lys Lys Gln Leu Val Glu Ile Glu Lys Val Val Leu His Pro Asn Tyr170 175 180cac cag gta gat att ggg ctc atc aaa ctc aaa cag aag gtg ctt gtt 630His Gln Val Asp Ile Gly Leu Ile Lys Leu Lys Gln Lys Val Leu Val185 190 195 200aat gag aga gtg atg ccc atc tgc cta cct tca aag aat tat gca gaa 678Asn Glu Arg Val Met Pro Ile Cys Leu Pro Ser Lys Asn Tyr Ala Glu205 210 215gta ggg cgt gtg ggt tac gtg tct ggc tgg gga caa agt gac aac ttt 726Val Gly Arg Val Gly Tyr Val Ser Gly Trp Gly Gln Ser Asp Asn Phe220 225 230aaa ctt act gac cat ctg aag tat gtc atg ctg cat gtg gct gac caa 774Lys Leu Thr Asp His Leu Lys Tyr Val Met Leu Pro Val Ala Asp Gln235 240 245tac gat tgc ata acg cat tat gaa ggc agc aca tgc ccc aaa tgg aag 822Tyr Asp Cys Ile Thr His Tyr Glu Gly Ser Thr Cys Pro Lys Trp Lys250 255 260gca ccg aag agc cct gta ggg gtg cag ccc ata ctg aac gaa cac acc 870Ala Pro Lys Ser Pro Val Gly Val Gln Pro Ile Leu Asn Glu His Thr265 270 275 280ttc tgt gtc ggc atg tct aag tac cag gaa gac acc tgc tat ggc gat 918
Phe Cys Val Gly Met Ser Lys Tyr Gln Glu Asp Thr Cys Tyr Gly Asp285 290 295gcg ggc agt gcc ttt gcc gtt cac gac ctg gag gag gac acc tgg tac 966Ala Gly Ser Ala Phe Ala Val His Asp Leu Glu Glu Asp Thr Trp Tyr300 305 310gcg gct ggg atc cta agc ttt gat aag agc tgt gct gtg gct gag tat 1014Ala Ala Gly Ile Leu Ser Phe Asp Lys Ser Cys Ala Val Ala Glu Tyr315 320 325ggt gtg tat gtg aag gtg act tcc atc cag cac tgg gtt cag aag acc 1062Gly Val Tyr Val Lys Val Thr Ser Ile Gln His Trp Val Gln Lys Thr330 335 340ata gct gag aac taa tgcaaggctg gccggaagcc cttgcctgaa agcaagattt 1117Ile Ala Glu Asn *345cagcctggaa gagggcaaag tggacgggag tggacaggag tggatgcgat aagatgtggt 1177ttgaagctga tgggtgccag ccctgcattg ctgagtcaat caataaagag ctttcttttg 1237acccaaaa 1245<210>15<211>1389<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(1)...(1389)<400>15atg gct agg gta ctg gga gca ccc gtt gca ctg ggg ttg tgg agc cta 48Met Ala Arg Val Leu Gly Ala Pro Val Ala Leu Gly Leu Trp Ser Leu1 5 10 15tgc tgg tct ctg gcc att gcc acc cct ctt cct ccg act agt gcc cat 96Cys Trp Ser Leu Ala Ile Ala Thr Pro Leu Pro Pro Thr Ser Ala His20 25 30ggg aat gtt gct gaa ggc gag acc aag cca gac cca gac gtg act gaa 144Gly Asn Val Ala Glu Gly Glu Thr Lys Pro Asp Pro Asp Val Thr Glu35 40 45
cgc tgc tca gat ggc tgg agc ttt gat gct acc acc ctg gat gac aat 192Arg Cys Ser Asp Gly Trp Ser Phe Asp Ala Thr Thr Leu Asp Asp Asn50 55 60gga acc atg ctg ttt ttt aaa ggg gag ttt gtg tgg aag agt cac aaa 240Gly Thr Met Leu Phe Phe Lys Gly Glu Phe Val Trp Lys Ser His Lys65 70 75 80tgg gac cgg gag tta atc tca gag aga tgg aag aat ttc ccc agc cct 288Trp Asp Arg Glu Leu Ile Ser Glu Arg Trp Lys Asn Phe Pro Ser Pro85 90 95gtg gat gct gca ttc cgt caa ggt cac aac agt gtc ttt ctg atc aag 336Val Asp Ala Ala Phe Arg Gln Gly His Asn Ser Val Phe Leu Ile Lys100 105 110ggg gac aaa gtc tgg gta tac cct cct gaa aag aag gag aaa gga tac 384Gly Asp Lys Val Trp Val Tyr Pro Pro Glu Lys Lys Glu Lys Gly Tyr115 120 125cca aag ttg ctc caa gat gaa ttt cct gga atc cca tcc cca ctg gat 432Pro Lys Leu Leu Gln Asp Glu Phe Pro Gly Ile Pro Ser Pro Leu Asp130 135 140gca gct gtg gaa tgt cac cgt gga gaa tgt caa gct gaa ggc gtc ctc 480Ala Ala Val Glu Cys His Arg Gly Glu Cys Gln Ala Glu Gly Val Leu145 150 155 160ttc ttc caa ggt gac cgc gag tgg ttc tgg gac ttg gct acg gga acc 528Phe Phe Gln Gly Asp Arg Glu Trp Phe Trp Asp Leu Ala Thr Gly Thr165 170 175atg aag gag cgt tcc tgg cca gct gtt ggg aac tgc tcc tct gcc ctg 576Met Lys Glu Arg Ser Trp Pro Ala Val Gly Asn Cys Ser Ser Ala Leu180 185 190aga tgg ctg ggc cgc tac tac tgc ttc cag ggt aac caa ttc ctg cgc 624Arg Trp Leu Gly Arg Tyr Tyr Cys Phe Gln Gly Asn Gln Phe Leu Arg195 200 205ttc gac cct gtc agg gga gag gtg cct ccc agg tac ccg cgg gat gtc 672Phe Asp Pro Val Arg Gly Glu Val Pro Pro Arg Tyr Pro Arg Asp Val210 215 220
cga gac tac ttc atg ccc tgc cct ggc aga ggc cat gga cac agg aat 720Arg Asp Tyr Phe Met Pro Cys Pro Gly Arg Gly His Gly His Arg Asn225 230 235 240ggg act ggc cat ggg aac agt acc cac cat ggc cct gag tat atg cgc 768Gly Thr Gly His Gly Asn Ser Thr His His Gly Pro Glu Tyr Met Arg245 250 255tgt agc cca cat cta gtc ttg tct gca ctg acg tct gac aac cat ggt 816Cys Ser Pro His Leu Val Leu Ser Ala Leu Thr Ser Asp Asn His Gly260 265 270gcc acc tat gcc ttc agt ggg acc cac tac tgg cgt ctg gac acc agc 864Ala Thr Tyr Ala Phe Ser Gly Thr His Tyr Trp Arg Leu Asp Thr Ser275 280 285cgg gat ggc tgg cat agc tgg ccc att gct cat cag tgg ccc cag ggt 912Arg Asp Gly Trp His Ser Trp Pro Ile Ala His Gln Trp Pro Gln Gly290 295 300cct tca gca gtg gat gct gcc ttt tcc tgg gaa gaa aaa ctc tat ctg 960Pro Ser Ala Val Asp Ala Ala Phe Ser Trp Glu Glu Lys Leu Tyr Leu305 310 315 320gtc cag ggc acc cag gta tat gtc ttc ctg aca aag gga ggc tat acc 1008Val Gln Gly Thr Gln ValTyr Val Phe Leu Thr Lys Gly Gly Tyr Thr325330 335cta gta agc ggt tat ccg aag cgg ctg gag aag gaa gtc ggg acc cct 1056Leu Val Ser Gly Tyr Pro Lys Arg Leu Glu Lys Glu Val Gly Thr Pro340 345 350cat ggg att atc ctg gac tct gtg gat gcg gcc ttt atc tgc cct ggg 1104His Gly Ile Ile Leu Asp Ser Val Asp Ala Ala Phe Ile Cys Pro Gly355 360 365tct tct cgg ctc cat atc atg gca gga cgg cgg ctg tgg tgg ctg gac 1152Ser Ser Arg Leu His Ile Met Ala Gly Arg Arg Leu Trp Trp Leu Asp370 375 380ctg aag tca gga gcc caa gcc acg tgg aca gag ctt cct tgg ccc cat 1200Leu Lys Ser Gly Ala Gln Ala Thr Trp Thr Glu Leu Pro Trp Pro His385 390 395 400
gag aag gta gac gga gcc ttg tgt atg gaa aag tcc ctt ggc cct aac 1248Glu Lys Val Asp Gly Ala Leu Cys Met Glu Lys Ser Leu Gly Pro Asn405 410 415tca tgt tcc gcc aat ggt ccc ggc ttg tac ctc atc cat ggt ccc aat 1296Ser Cys Ser Ala Asn Gly Pro Gly Leu Tyr Leu Ile His Gly Pro Asn420 425 430ttg tac tgc tac agt gat gtg gag aaa ctg aat gca gcc aag gcc ctt 1344Leu Tyr Cys Tyr Ser Asp Val Glu Lys Leu Asn Ala Ala Lys Ala Leu435 440 445ccg caa ccc cag aat gtg acc agt ctc ctg ggc tgc act cac tga 1389Pro Gln Pro Gln Asn Val Thr Ser Leu Leu Gly Cys Thr His *450 455 460<210>16<211>3260<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(37)...(2829)<400>16gagttcagaa gcctcctggc agacactgga gccacg atg aag ccc cca agg cct 54Met Lys Pro Pro Arg Pro1 5gtc cgt acc tgc agc aaa gtt ctc gtc ctg ctt tca ctg ctg gcc atc 102Val Arg Thr Cys Ser Lys Val Leu Val Leu Leu Ser Leu Leu Ala Ile10 15 20cac cag act act act gcc gaa aag aat ggc atc gac atc tac agc ctc 150His Gln Thr Thr Thr Ala Glu Lys Asn Gly Ile Asp Ile Tyr Ser Leu25 30 35acc gtg gac tcc agg gtc tca tcc cga ttt gcc cac acg gtc gtc acc 198Thr Val Asp Ser Arg Val Ser Ser Arg Phe Ala His Thr Val Val Thr40 45 50
agc cga gtg gtc aat agg gcc aat act gtg cag gag gcc acc ttc cag 246Ser Arg Val Val Asn Arg Ala Asn Thr Val Gln Glu Ala Thr Phe Gln55 60 65 70atg gag ctg ccc aag aaa gcc ttc atc acc aac ttc tcc atg atc atc 294Met Glu Leu Pro Lys Lys Ala Phe Ile Thr Asn Phe Ser Met Ile Ile75 80 85gat ggc atg acc tac cca ggg atc atc aag gag aag gct gaa gcc cag 342Asp Gly Met Thr Tyr Pro Gly Ile Ile Lys Glu Lys Ala Glu Ala Gln90 95 100gca cag tac agc gca gca gtg gcc aag gga aag agc gct ggc ctc gtc 390Ala Gln Tyr Ser Ala Ala Val Ala Lys Gly Lys Ser Ala Gly Leu Val105 110 115aag gcc acc ggg aga aac atg gag cag ttc cag gtg tcg gtc agt gtg 438Lys Ala Thr Gly Arg Asn Met Glu Gln Phe Gln Val Ser Val Ser Val120 125 130gct ccc aat gcc aag atc acc ttt gag ctg gtc tat gag gag ctg ctc 486Ala Pro Asn Ala Lys Ile Thr Phe Glu Leu Val Tyr Glu Glu Leu Leu135 140 145 150aag cgg cgt ttg ggg gtg tac gag ctg ctg ctg aaa gtg cgg ccc cag 534Lys Arg Arg Leu Gly Val Tyr Glu Leu Leu Leu Lys Val Arg Pro Gln155 160 165cag ctg gtc aag cac ctg cag atg gac att cac atc ttc gag ccc cag 582Gln Leu Val Lys His Leu Gln Met Asp Ile His Ile Phe Glu Pro Gln170 175 180ggc atc agc ttt ctg gag aca gag agc acc ttc atg acc aac cag ctg 630Gly Ile Ser Phe Leu Glu Thr Glu Ser Thr Phe Met Thr Asn Gln Leu185 190 195gta gac gcc ctc acc acc tgg cag aat aag acc aag gct cac atc cgg 678Val Asp Ala Leu Thr Thr Trp Gln Asn Lys Thr Lys Ala His Ile Arg200 205 210ttc aag cca aca ctt tcc cag cag caa aag tcc cca gag cag caa gaa 726Phe Lys Pro Thr Leu Ser Gln Gln Gln Lys Ser Pro Glu Gln Gln Glu215 220 225 230
aca gtc ctg gac ggc aac ctc att atc cgc tat gat gtg gac cgg gcc 774Thr Val Leu Asp Gly Asn Leu Ile Ile Arg Tyr Asp Val Asp Arg Ala235 240 245atc tcc ggg ggc tcc att cag atc gag aac ggc tac ttt gta cac tac 822Ile Ser Gly Gly Ser Ile Gln Ile Glu Asn Gly Tyr Phe Val His Tyr250 255 260ttt gcc ccc gag ggc cta acc aca atg ccc aag aat gtg gtc ttt gtc 870Phe Ala Pro Glu Gly Leu Thr Thr Met Pro Lys Asn Val Val Phe Val265 270 275att gac aag agc ggc tcc atg agt ggc agg aaa atc cag cag acc cgg 918Ile Asp Lys Ser Gly Ser Met Ser Gly Arg Lys Ile Gln Gln Thr Arg280 285 290gaa gcc cta atc aag atc ctg gat gac ctc agc ccc aga gac cag ttc 966Glu Ala Leu Ile Lys Ile Leu Asp Asp Leu Ser Pro Arg Asp Gln Phe295 300 305 310aac ctc atc gtc ttc agt aca gaa gca act cag tgg agg cca tca ctg 1014Asn Leu Ile Val Phe Ser Thr Glu Ala Thr Gln Trp Arg Pro Ser Leu315 320 325gtg cca gcc tca gcc gag aac gtg aac aag gcc agg agc ttt gct gcg 1062Val Pro Ala Ser Ala Glu Asn Val Asn Lys Ala Arg Ser Phe Ala Ala330 335 340ggc atc cag gcc ctg gga ggg acc aac atc aat gat gca atg ctg atg 1110Gly Ile Gln Ala Leu Gly Gly Thr Asn Ile Asn Asp Ala Met Leu Met345 350 355gct gtg cag ttg ctg gac agc agc aac cag gag gag cgg ctg ccc gaa 1158Ala Val Gln Leu Leu Asp Ser Ser Asn Gln Glu Glu Arg Leu Pro Glu360 365 370ggg agt gtc tca ctc atc atc ctg ctc acc gat ggc gac ccc act gtg 1206Gly Ser Val Ser Leu Ile Ile Leu Leu Thr Asp Gly Asp Pro Thr Val375 380 385 390ggg gag act aac ccc agg agc atc cag aat aac gtg cgg gaa gct gta 1254Gly Glu Thr Asn Pro Arg Ser Ile Gln Asn Asn Val Arg Glu Ala Val395 400 405
agt ggc cgg tac agc ctc ttc tgc ctg ggc ttc ggt ttc gac gtc agc 1302Ser Gly Arg Tyr Ser Leu Phe Cys Leu Gly Phe Gly Phe Asp Val Ser410 415 420tat gcc ttc ctg gag aag ctg gca ctg gac aat ggc ggc ctg gcc cgg 1350Tyr Ala Phe Leu Glu Lys Leu Ala Leu Asp Ash Gly Gly Leu Ala Arg425 430 435cgc atc cat gag gac tca gac tct gcc ctg cag ctc cag gac ttc tac 1398Arg Ile His Glu Asp Ser Asp Ser Ala Leu Gln Leu Gln Asp Phe Tyr440 445 450cag gaa gtg gcc aac cca ctg ctg aca gca gtg acc ttc gag tac cca 1446Gln Glu Val Ala Asn Pro Leu Leu Thr Ala Val Thr Phe Glu Tyr Pro455 460 465 470agc aat gcc gtg gag gag gtc act cag aac aac ttc cgg ctc ctc ttc 1494Ser Asn Ala Val Glu Glu Val Thr Gln Asn Asn Phe Arg Leu Leu Phe475 480 485aag ggc tca gag atg gtg gtg gct ggg aag ctc cag gac cgg ggg cct 1542Lys Gly Ser Glu Met Val Val Ala Gly Lys Leu Gln Asp Arg Gly Pro490 495 500gat gtg ctc aca gcc aca gtc agt ggg aag ctg cct aca cag aac atc 1590Asp Val Leu Thr Ala Thr Val Ser Gly Lys Leu Pro Thr Gln Asn Ile505 510 515act ttc caa acg gag tcc agt gtg gca gag cag gag gcg gag ttc cag 1638Thr Phe Gln Thr Glu Ser Ser Val Ala Glu Gln Glu Ala Glu Phe Gln520 525 530agc ccc aag tat atc ttc cac aac ttc atg gag agg ctc tgg gca tac 1686Ser Pro Lys Tyr Ile Phe His Asn Phe Met Glu Arg Leu Trp Ala Tyr535 540 545 550ctg act atc cag cag ctg ctg gag caa act gtc tcc gca tcc gat gct 1734Leu Thr Ile Gln Gln Leu Leu Glu Gln Thr Val Ser Ala Ser Asp Ala555 560 565gat cag cag gcc ctc cgg aac caa gcg ctg aat tta tca ctt gcc tac 1782Asp Gln Gln Ala Leu Arg Asn Gln Ala Leu Asn Leu Ser Leu Ala Tyr570 575 580
agc ttt gtc acg cct ctc aca tct atg gta gtc acc aaa ccc gat gac 1830Ser Phe Val Thr Pro Leu Thr Ser Met Val Val Thr Lys Pro Asp Asp585 590 595caa gag cag tct caa gtt gct gag aag ccc atg gaa ggc gaa agt aga 1878Gln Glu Gln Ser Gln Val Ala Glu Lys Pro Met Glu Gly Glu Ser Arg600 605 610aac agg aat gtc cac tca ggt tcc act ttc ttc aaa tat tat ctc cag 1926Asn Arg Asn Val His Ser Gly Ser Thr Phe Phe Lys Tyr Tyr Leu Gln615 620 625 630gga gca aaa ata cca aaa cca gag gct tcc ttt tct cca aga aga gga 1974Gly Ala Lys Ile Pro Lys Pro Glu Ala Ser Phe Ser Pro Arg Arg Gly635 640 645tgg aat aga caa gct gga gct gct ggc tcc cgg atg aat ttc aga cct 2022Trp Asn Arg Gln Ala Gly Ala Ala Gly Ser Arg Met Asn Phe Arg Pro650 655 660ggg gtt ctc agc tcc agg caa ctt gga ctc cca gga cct cct gat gtt 2070Gly Val Leu Ser Ser Arg Gln Leu Gly Leu Pro Gly Pro Pro Asp Val665 670 675cct gac cat gct gct tac cac ccc ttc cgc cgt ctg gcc atc ttg cct 2118Pro Asp His Ala Ala Tyr His Pro Phe Arg Arg Leu Ala Ile Leu Pro680 685 690gct tca gca cca cca gcc acc tca aat cct gat cca gct gtg tct cgt 2166Ala Ser Ala Pro Pro Ala Thr Ser Asn Pro Asp Pro Ala Val Ser Arg695 700 705 710gtc atg aat atg aaa atc gaa gaa aca acc atg aca acc caa acc cca 2214Val Met Asn Met Lys Ile Glu Glu Thr Thr Met Thr Thr Gln Thr Pro715 720 725gcc ccc ata cag gct ccc tct gcc atc ctg cca ctg cct ggg cag agt 2262Ala Pro Ile Gln Ala Pro Ser Ala Ile Leu Pro Leu Pro Gly Gln Ser730 735 740gtg gag cgg ctc tgt gtg gac ccc aga cac cgc cag ggg cca gtg aac 2310Val Glu Arg Leu Cys Val Asp Pro Arg His Arg Gln Gly Pro Val Asn745 750 755
ctg ctc tca gac cct gag caa ggg gtt gag gtg act ggc cag tat gag 2358Leu Leu Ser Asp Pro Glu Gln Gly Val Glu Val Thr Gly Gln Tyr Glu760 765 770agg gag aag gct ggg ttc tca tgg atc gaa gtg acc ttc aag aac ccc 2406Arg Glu Lys Ala Gly Phe Ser Trp Ile Glu Val Thr Phe Lys Asn Pro775 780 785 790ctg gta tgg gtt cac gca tcc cct gaa cac gtg gtg gtg act cgg aac 2454Leu Val Trp Val His Ala Ser Pro Glu His Val Val Val Thr Arg Asn795 800 805cga aga agc tct gcg tac aag tgg aag gag acg cta ttc tca gtg atg 2502Arg Arg Ser Ser Ala Tyr Lys Trp Lys Glu Thr Leu Phe Ser Val Met810 815 820ccc ggc ctg aag atg acc atg gac aag acg ggt ctc ctg ctg ctc agt 2550Pro Gly Leu Lys Met Thr Met Asp Lys Thr Gly Leu Leu Leu Leu Ser825 830 835gac cca gac aaa gtg acc atc ggc ctg ttg ttc tgg gat ggc cgt ggg 2598Asp Pro Asp Lys Val Thr Ile Gly Leu Leu Phe Trp Asp Gly Arg Gly840 845 850gag ggg ctc cgg ctc ctt ctg cgt gac act gac cgc ttc tcc agc cac 2646Glu Gly Leu Arg Leu Leu Leu Arg Asp Thr Asp Arg Phe Ser Ser His855 860 865 870gtt gga ggg acc ctt ggc cag ttt tac cag gag gtg ctc tgg gga tct 2694Val Gly Gly Thr Leu Gly Gln Phe Tyr Gln Glu Val Leu Trp Gly Ser875 880 885cca gca gca tca gat gac ggc aga cgc acg ctg agg gtt cag ggc aat 2742Pro Ala Ala Ser Asp Asp Gly Arg Arg Thr Leu Arg Val Gln Gly Asn890 895 900gac cac tct gcc acc aga gag cgc agg ctg gat tac cag gag ggg ccc 2790Asp His Ser Ala Thr Arg Glu Arg Arg Leu Asp Tyr Gln Glu Gly Pro905 910 915ccg gga gtg gag att tcc tgc tgg tct gtg gag ctg tag ttctgatgga2839Pro Gly Val Glu Ile Ser Cys Trp Ser Val Glu Leu *920 925 930
aggagctgtg cccaccctgt acacttggct tccccctgca actgcagggc cgcttctggg 2899gcctggacca ccatggggag gaagagtccc actcattaca aataaagaaa ggtggtgtga 2959gcctgggaag tgggtgtctc cagttccatg tggccaaatc ctagggcctc aacctcgcat 3019cctgaacctt agcatcgtgg aacacagaag cttccactgt cagctctcaa gagcccatgg 3079ccaggaaggc ccatgctgag ctttcagtcc agccccttca ttttacaaac aaggaaactg 3139agctcgaacc acccatttga gatgtcactg tggcccccag ctagaggccc agggctggga 3199gcattctcca ggagcagagg ttcagtctgc ttcatggtct cttggaccag ttttgactac 3259a 3260<210>17<211>1652<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(73)...(570)<400>17aaaaggggcg ggaggccagg ctcgtgccgt tttgcagacg ccaccgccga ggaaaaccgt 60gtactattag cc atg gtc aac ccc acc gtg ttc ttc gac att gcc gtc gac 111Met Val Asn Pro Thr Val Phe Phe Asp Ile Ala Val Asp1 5 10ggc gag ccc ttg ggc cgc gtc tcc ttt gag ctg ttt gca gac aag gtc 159Gly Glu Pro Leu Gly Arg Val Ser Phe Glu Leu Phe Ala Asp Lys Val15 20 25cca aag aca gca gaa aat ttt cgt gct ctg agc act gga gag aaa gga 207Pro Lys Thr Ala Glu Asn Phe Arg Ala Leu Ser Thr Gly Glu Lys Gly30 35 40 45ttt ggt tat aag ggt tcc tgc ttt cac aga att att cca ggg ttt atg 255Phe Gly Tyr Lys Gly Ser Cys Phe His Arg Ile Ile Pro Gly Phe Met50 55 60tgt cag ggt ggt gac ttc aca cgc cat aat ggc act ggt ggc aag tcc 303Cys Gln Gly Gly Asp Phe Thr Arg His Asn Gly Thr Gly Gly Lys Ser65 70 75atc tat ggg gag aaa ttt gaa gat gag aac ttc atc cta aag cat acg 351Ile Tyr Gly Glu Lys Phe Glu Asp Glu Asn Phe Ile Leu Lys His Thr80 85 90
ggt cct ggc atc ttg tcc atg gca aat gct gga ccc aac aca aat ggt399Gly Pro Gly Ile Leu Ser Met Ala Asn Ala Gly Pro Asn Thr Asn Gly95 100 105tcc cag ttt ttc atc tgc act gcc aag act gag tgg ttg gat ggc aag447Ser Gln Phe Phe Ile Cys Thr Ala Lys Thr Glu Trp Leu Asp Gly Lys110 115 120 125cat gtg gtg ttt ggc aaa gtg aaa gaa ggc atg aat att gtg gag gcc495His Val Val Phe Gly Lys Val Lys Glu Gly Met Asn Ile Val Glu Ala130 135 140atg gag cgc ttt ggg tcc agg aat ggc aag acc agc aag aag atc acc543Met Glu Arg Phe Gly Ser Arg Asn Gly Lys Thr Ser Lys Lys Ile Thr145 150 155att gct gac tgt gga caa ctc gaa taa gtttgacttg tgttttatct 590Ile Ala Asp Cys Gly Gln Leu Glu *160 165taaccaccag atcattcctt ctgtagctca ggagagcacc cctccacccc atttgctcgc 650agtatcctag aatctttgtg ctctcgctgc agttcccttt gggttccatg ttttccttgt 710tccctcccat gcctagctgg attgcagagt taagtttatg attatgaaat aaaaactaaa 770taacaattgt cctcgtttga gttaagagtg ttgatgtagg ctttatttta agcagtaatg 830ggttacttct gaaacatcac ttgtttgctt aattctacac agtacttaga ttttttttac 890tttccagtcc caggaagtgt caatgtttgt tgagtggaat attgaaaatg taggcagcaa 950ctgggcatgg tggctcactg tctgtaatgt attacctgag gcagaagacc acctgagggt 1010aggagtcaag atcagcctgg gcaacatagt gagacgctgt ctctacaaaa aataattagc 1070ctggcctggt ggtgcatgcc tagtcctagc tgatctggag gctgacgtgg gaggattgct 1130tgagcctaga gtgagctatt atcatgccac tgtacagcct gggtgttcac agatcttgtg 1190tctcaaaggt aggcagaggc aggaaaagca aggagccaga attaagaggt tgggtcagtc 1250tgcagtgagt tcatgcattt agaggtgttc ttcaagatga ctaatgtcaa aaattgagac 1310atctgttgcg gttttttttt tttttttttc ccctggaatg cagtggcgtg atctcagctc 1370actgcagcct ccgcctcctg ggttcaagtg attctagtgc ctcagcctcc tgagtagctg 1430ggataacggg cgtgtgccac catgcccagc taatttttgt atttttagta tagatggggt 1490ttcatcattt tgaccaggct ggtctcaaac tcttgacctc agctgatgcg cctgccttgg 1550cctcccaaac tgctgagatt acagatgtga gccaccgcac cctacctcat tttctgtaac 1610aaagctaagc ttgaacactg ttgatgttct tgagggaagc at 1652<210>18<211>1856<212>DNA<213>人類(lèi)
<220>
<221>CDS<222>(299)...(979)<400>18agccaaaaga ggaagggacc ggcctcccac gtccacaggg acctgacttc cacctctctg 60cccagatttg cttatgtcac tgtcgccccg ggacggggag gtggggagct gagggcaagt 120cgcgcccgcc cctgaaatcc cagccgccta gcgattggct gcaagggtct cggcttggcc 180gcggattaat cacacccgag ggcttgaaag gtggctggga gcgccggaca cctcagacgg 240acggtggcca gggatcaggc agcggctcag gcgaccctga gtgtgccccc accccgcc 298atg gcc cgg ctg ctg cag gcg tcc tgc ctg ctt tcc ctg ctc ctg gcc 346Met Ala Arg Leu Leu Gln Ala Ser Cys Leu Leu Ser Leu Leu Leu Ala1 5 10 15ggc ttc gtc tcg cag agc cgg gga caa gag aag tcg aag atg gac tgc 394Gly Phe Val Ser Gln Ser Arg Gly Gln Glu Lys Ser Lys Met Asp Cys20 25 30cat ggt ggc ata agt ggc acc att tac gag tac gga gcc ctc acc att 442His Gly Gly Ile Ser Gly Thr Ile Tyr Glu Tyr Gly Ala Leu Thr Ile35 40 45gat ggg gag gag tac atc ccc ttc aag cag tat gct ggc aaa tac gtc 490Asp Gly Glu Glu Tyr Ile Pro Phe Lys Gln Tyr Ala Gly Lys Tyr Val50 55 60ctc ttt gtc aac gtg gcc agc tac tga ggc ctg acg ggc cag tac att 538Leu Phe Val Asn Val Ala Ser Tyr * Gly Leu Thr Gly Gln Tyr Ile65 70 75gaa ctg aat gca cta cag gaa gag ctt gca cca ttc ggt ctg gtc att 586Glu Leu Asn Ala Leu Gln Glu Glu Leu Ala Pro Phe Gly Leu Val Ile80 85 90 95ctg ggc ttt ccc tgc aac caa ttt gga aaa cag gaa cca gga gag aac 634Leu Gly Phe Pro Cys Asn Gln Phe Gly Lys Gln Glu Pro Gly Glu Asn100 105 110tca gag atc ctt cct acc ctc aag tat gtc cga cca ggt gga ggc ttt 682Ser Glu Ile Leu Pro Thr Leu Lys Tyr Val Arg Pro Gly Gly Gly Phe115 120 125gtc cct aat ttc cag ctc ttt gag aaa ggg gat gtc aat gga gag aaa 730
Val Pro Asn Phe Gln Leu Phe Glu Lys Gly Asp Val Asn Gly Glu Lys130 135 140gag cag aaa ttc tac act ttc cta aag aac tcc tgt cct ccc acc tcg778Glu Gln Lys Phe Tyr Thr Phe Leu Lys Asn Ser Cys Pro Pro Thr Ser145 150 155gag ctc ctg ggt aca tct gac cgc ctc ttc tgg gaa ccc atg aag gtt826Glu Leu Leu Gly Thr Ser Asp Arg Leu Phe Trp Glu Pro Met Lys Val160 165 170 175cac gac atc cgc tgg aac ttt gag aag ttc ctg gtg ggg cca gat ggt874His Asp Ile Arg Trp Asn Phe Glu Lys Phe Leu Val Gly Pro Asp Gly180 185 190ata ccc atc atg cgc tgg cac cac cgg acc acg gtc agc aac gtc aag922Ile Pro Ile Met Arg Trp His His Arg Thr Thr Val Ser Asn Val Lys195 200 205atg gac atc ctg tcc tac atg agg cgg cag gca gcc ctg ggg gtc aag970Met Asp Ile Leu Ser Tyr Met Arg Arg Gln Ala Ala Leu Gly Val Lys210 215 220agg aag taa ctgaaggccg tctcatccca tgtccaccat gtaggggagg1019Arg Lys *225gactttgttc aggaagaaat ccgtgtctcc aaccacacta tctacccatc acagacccct 1079ttcctatcac tcaaggcccc agcctggcac aaatggatgc atacagttct gtgtactgcc 1139aggcatgtgg gtgtgggtgc aatgtgggtg tttacacaca tgcctacagg tatgcgtgat 1199tgtgtgtgtg tgcatgggtg tacagccacg tgtctaccta tgtgtctttc tgggaatgtg 1259taccatctgt gtgcctgcag ctgtgtagtg ctggacagtg acaacccttt ctctccagtt 1319ctccactcca atgataatag ttcacttata cctaaaccca aaggaaaaac cagctctagg 1379tccaattgtt ctgctctaac tgatacctca accttggggc cagcatctcc cactgcctcc 1439aaatattagt aactatgact gacgtcccca gaagtttctg ggtctaccac actccccaac 1499cccccactcc tacttcctga agggccctcc caaggctaca tccccacccc acagttctcc 1559ctgagagaga tcaacctccc tgagatcaac caaggcagat gtgacagcaa gggccacgga 1619ccccatggca ggggtggcgt cttcatgagg gaggggccca aagcccttgt gggcggacct 1679cccctgagcc tgtctgaggg gccagccctt agtgcattca ggctaaggcc cctgggcagg 1739gatgccaccc ctgctccttc ggaggacgtg ccctcacccc tcactggtcc actggcttga 1799gactcacccc gtctgcccag taaaagcctt tctgcagcaa aaaaaaaaaa aaaaaaa 1856<210>19<211>715
<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(81)...(467)<400>19tgcagacttg taggcagcaa ctcaccctca ctcagaggtc ttctggttct ggaaacaact 60ctagctcagc cttctccacc atg agc ctc aga ctt gat acc acc cct tcc tgt 113Met Ser Leu Arg Leu Asp Thr Thr Pro Ser Cys1 5 10aac agt gcg aga cca ctt cat gcc ttg cag gtg ctg ctg ctt ctg tca 161Asn Ser Ala Arg Pro Leu His Ala Leu Gln Val Leu Leu Leu Leu Ser15 20 25ttg ctg ctg act gct ctg gct tcc tcc acc aaa gga caa act aag aga 209Leu Leu Leu Thr Ala Leu Ala Ser Ser Thr Lys Gly Gln Thr Lys Arg30 35 40aac ttg gcg aaa ggc aaa gag gaa agt cta gac agt gac ttg tat gct 257Asn Leu Ala Lys Gly Lys Glu Glu Ser Leu Asp Ser Asp Leu Tyr Ala45 50 55gaa ctc cgc tgc atg tgt ata aag aca acc tct gga att cat ccc aaa 305Glu Leu Arg Cys Met Cys Ile Lys Thr Thr Ser Gly Ile His Pro Lys60 65 70 75aac atc caa agt ttg gaa gtg atc ggg aaa gga acc cat tgc aac caa 353Asn Ile Gln Ser Leu Glu Val Ile Gly Lys Gly Thr His Cys Asn Gln80 85 90gtc gaa gtg ata gcc aca ctg aag gat ggg agg aaa atc tgc ctg gac 401Val Glu Val Ile Ala Thr Leu Lys Asp Gly Arg Lys Ile Cys Leu Asp95 100 105cca gat gct ccc aga atc aag aaa att gta cag aaa aaa ttg gca ggt 449Pro Asp Ala Pro Arg Ile Lys Lys Ile Val Gln Lys Lys Leu Ala Gly110 115 120gat gaa tct gct gat taa tttgttctgt ttctgccaaa cttctttaac 497Asp Glu Ser Ala Asp *125
tcccaggaag ggtagaattt tgaaaccttg attttctaga gttctcattt attcaggata 557cctattctta ctgtattaaa atttggatat gtgtttcatt ctgtctcaaa aatcacattt 617tattctgaga aggttggtta aaagatggca gaaagaagat gaaaataaat aagcctggtt 677tcaaccctct aattcttgcc taaaaaaaaa aaaaaaaa 715<210>20<211>2318<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(51)...(2147)<400>20gcacagaagc gagtccgact gtgctcgctg ctcagcgccg cacccggaag atg agg56Met Arg1ctc gcc gtg gga gcc ctg ctg gtc tgc gcc gtc ctg ggg ctg tgt ctg 104Leu Ala Val Gly Ala Leu Leu Val Cys Ala Val Leu Gly Leu Cys Leu5 10 15gct gtc cct gat aaa act gtg aga tgg tgt gca gtg tcg gag cat gag 152Ala Val Pro Asp Lys Thr Val Arg Trp Cys Ala Val Ser Glu His Glu20 25 30gcc act aag tgc cag agt ttc cgc gac cat atg aaa agc gtc att cca 200Ala Thr Lys Cys Gln Ser Phe Arg Asp His Met Lys Ser Val Ile Pro35 40 45 50tcc gat ggt ccc agt gtt gct tgt gtg aag aaa gcc tcc tac ctt gat 248Ser Asp Gly Pro Ser Val Ala Cys Val Lys Lys Ala Ser Tyr Leu Asp55 60 65tgc atc agg gcc att gcg gca aac gaa gcg gat gct gtg aca ctg gat 296Cys Ile Arg Ala Ile Ala Ala Asn Glu Ala Asp Ala Val Thr Leu Asp70 75 80gca ggt ttg gtg tat gat gct tac ctg gct ccc aat aac ctg aag cct 344Ala Gly Leu Val Tyr Asp Ala Tyr Leu Ala Pro Asn Asn Leu Lys Pro85 90 95
gtg gtg gca gag ttc tat ggg tca aaa gag gat cca cag act ttc tat 392Val Val Ala Glu Phe Tyr Gly Ser Lys Glu Asp Pro Gln Thr Phe Tyr100 105 110tat gct gtt gct gtg gtg aag aag gat agt ggc ttc cag atg aac cag 440Tyr Ala Val Ala Val Val Lys Lys Asp Ser Gly Phe Gln Met Asn Gln115 120 125 130ctt cga ggc aag aag tcc tgc cac acg ggt cta ggc agg tcc gct ggg 488Leu Arg Gly Lys Lys Ser Cys His Thr Gly Leu Gly Arg Ser Ala Gly135 140 145tgg aac atc ccc ata ggc tta ctt tac tgt gac tta cct gag cca cgt 536Trp Asn Ile Pro Ile Gly Leu Leu Tyr Cys Asp Leu Pro Glu Pro Arg150 155 160aaa cct ctt gag aaa gca gtg gcc aat ttc ttc tcg ggc agc tgt gcc 584Lys Pro Leu Glu Lys Ala Val Ala Asn Phe Phe Ser Gly Ser Cys Ala165 170 175cct tgt gcg gat ggg acg gac tte ccc cag ctg tgt caa ctg tgt cca 632Pro Cys Ala Asp Gly Thr Asp Phe Pro Gln Leu Cys Gln Leu Cys Pro180 185 190ggg tgt ggc tgc tcc acc ctt aac caa tacttc ggc tac tcg gga gcc680Gly Cys Gly Cys Ser Thr Leu Asn Gln Tyr Phe Gly Tyr Ser Gly Ala195 200 205 210ttc aag tgt ctg aag gat ggt gct ggg gat gtg gcc ttt gtc aag cac 728Phe Lys Cys Leu Lys Asp Gly Ala Gly Asp Val Ala Phe Val Lys His215 220 225tcg act ata ttt gag aac ttg gca aac aag gct gac agg gac cag tat 776Ser Thr Ile Phe Glu Asn Leu Ala Asn Lys Ala Asp Arg Asp Gln Tyr230 235 240gag ctg ctt tgc ctg gac aac acc cgg aag ccg gta gat gaa tac aag 824Glu Leu Leu Cys Leu Asp Asn Thr Arg Lys Pro Val Asp Glu Tyr Lys245 250 255gac tgc cac ttg gcc cag gtc cct tct cat acc gtc gtg gcc cga agt 872Asp Cys His Leu Ala Gln Val Pro Ser His Thr Val Val Ala Arg Ser260 265 270
atg ggc ggc aag gag gac ttg atc tgg gag ctt ctc aac cag gcc cag 920Met Gly Gly Lys Glu Asp Leu Ile Trp Glu Leu Leu Asn Gln Ala Gln275 280 285 290gaa cat ttt ggc aaa gac aaa tca aaa gaa ttc caa cta ttc agc tct 968Glu His Phe Gly Lys Asp Lys Ser Lys Glu Phe Gln Leu Phe Ser Ser295 300 305cct cat ggg aag gac ctg ctg ttt aag gac tct gcc cac ggg ttt tta 1016Pro His Gly Lys Asp Leu Leu Phe Lys Asp Ser Aia His Gly Phe Leu310 315 320aaa gtc ccc ccc agg atg gat gcc aag atg tac ctg ggc tat gag tat 1064Lys Val Pro Pro Arg Met Asp Ala Lys Met Tyr Leu Gly Tyr Glu Tyr325 330 335gtc act gcc atc cgg aat cta cgg gaa ggc aca tgc cca gaa gcc cca 1112Val Thr Ala Ile Arg Asn Leu Arg Glu Gly Thr Cys Pro Glu Ala Pro340 345 350aca gat gaa tgc aag cct gtg aag tgg tgt gcg ctg agc cac cac gag 1160Thr Asp Glu Cys Lys Pro Val Lys Trp Cys Ala Leu Ser His His Glu355 360 365 370agg ctc aag tgt gat gag tgg agt gtt aac agt gta ggg aaa ata gag 1208Arg Leu Lys Cys Asp Glu Trp Ser Val Asn Ser Val Gly Lys Ile Glu375 380 385tgt gta tca gca gag acc acc gaa gac tgc atc gcc aag atc atg aat 1256Cys Val Ser Ala Glu Thr Thr Glu Asp Cys Ile Ala Lys Ile Met Asn390 395 400gga gaa gct gat gcc atg agc ttg gat gga ggg ttt gtc tac ata gcg 1304Gly Glu Ala Asp Ala Met Ser Leu Asp Gly Gly Phe Val Tyr Ile Ala405 410 415ggc aag tgt ggt ctg gtg cct gtc ttg gca gaa aac tac aat aag agc 1352Gly Lys Cys Gly Leu Val Pro Val Leu Ala Glu Asn Tyr Asn Lys Ser420 425 430gat aat tgt gag gat aca cca gag gca ggg tat ttt gct gta gca gtg 1400Asp Asn Cys Glu Asp Thr Pro Glu Ala Gly Tyr Phe Ala Val Ala Val435 440 445 450
gtg aag aaa tca gct tct gac ctc acc tgg gac aat ctg aaa ggc aag 1448Val Lys Lys Ser Ala Ser Asp Leu Thr Trp Asp Asn Leu Lys Gly Lys455 460 465aag tcc tgc cat acg gca gtt ggc aga acc gct ggc tgg aac atc ccc 1496Lys Ser Cys His Thr Ala Val Gly Arg Thr Ala Gly Trp Asn Ile Pro470 475 480atg ggc ctg ctc tac aat aag atc aac cac tgc aga ttt gat gaa ttt 1544Met Gly Leu Leu Tyr Asn Lys Ile Asn His Cys Arg Phe Asp Glu Phe485 490 495ttc agt gaa ggt tgt gcc cct ggg tct aag aaa gac tcc agt ctc tgt 1592Phe Ser Glu Gly Cys Ala Pro Gly Ser Lys Lys Asp Ser Ser Leu Cys500 505 510aag ctg tgt atg ggc tca ggc cta aac ctg tgt gaa ccc aac aac aaa 1640Lys Leu Cys Met Gly Ser Gly Leu Asn Leu Cys Glu Pro Asn Asn Lys515 520 525 530gag gga tac tac ggc tac aca ggc gct ttc agg tgt ctg gtt gag aag 1688Glu Gly Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Val Glu Lys535 540 545gga gat gtg gcc ttt gtg aaa cac cag act gtc cca cag aac act ggg 1736Gly Asp Val Ala Phe Val Lys His Gln Thr Val Pro Gln Asn Thr Gly550 555 560gga aaa aac cct gat cca tgg gct aag aat ctg aat gaa aaa gac tat 1784Gly Lys Asn Pro Asp Pro Trp Ala Lys Asn Leu Asn Glu Lys Asp Tyr565 570 575gag ttg ctg tgc ctt gat ggt acc agg aaa cct gtg gag gag tat gcg 1832Glu Leu Leu Cys Leu Asp Gly Thr Arg Lys Pro Val Glu Glu Tyr Ala580 585 590aac tgc cac ctg gcc aga gcc ccg aat cac gct gtg gtc aca cgg aaa 1880Asn Cys His Leu Ala Arg Ala Pro Asn His Ala Val Val Thr Arg Lys595 600 605 610gat aag gaa gct tgc gtc cac aag ata tta cgt caa cag cag cac cta 1928Asp Lys Glu Ala Cys Val His Lys Ile Leu Arg Gln Gln Gln His Leu615 620 625
ttt gga agc aac gtaact gac tgc tcg ggc aac ttt tgt ttg ttc cgg1976Phe Gly Ser Asn ValThr Asp Cys Ser Gly Asn Phe Cys Leu Phe Arg630635 640tcg gaa acc aag gac ctt ctg ttc aga gat gac aca gta tgt ttg gcc 2024Ser Glu Thr Lys Asp Leu Leu Phe Arg Asp Asp Thr Val Cys Leu Ala645 650 655aaa ctt cat gac aga aac aca tat gaa aaa tac tta gga gaa gaa tat 2072Lys Leu His Asp Arg Asn Thr Tyr Glu Lys Tyr Leu Gly Glu Glu Tyr660 665 670gtc aag gct gtt ggt aac ctg aga aaa tgc tcc acc tca tca ctc ctg 2120Val Lys Ala Val Gly Asn Leu Arg Lys Cys Ser Thr Ser Ser Leu Leu675680 685 690gaa gcc tgc act ttc cgt aga cct taa aatctcagag gtagggctgc 2167Glu Ala Cys Thr Phe Arg Arg Pro *695caccaaggtg aagatgggaa cgcagatgat ccatgagttt gccctggttt cactggccca 2227agtggtttgt gctaaccacg tctgtcttca cagctctgtg ttgccatgtg tgctgaacaa 2287aaaataaaaa ttattattga ttttatattt c2318<210>21<211>722<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(225)...(593)<400>21aaggctcagt ataaatagca gccaccgctc cctggcaggc agggacccgc agctcagcta 60cagcacagat caggtgagga gcacaccaag gagtgatttt taaaacttac tctgttttct 120ctttcccaac aagattatca tttcctttaa aaaaaatagt tatcctgggg catacagcca 180taccattctg aaggtgtctt atctcctctg atctagagag cacc atg aag ctt ctc 236Met Lys Leu Leu1acg ggc ctg gtt ttc tgc tcc ttg gtc ctg ggt gtc agc agc cga agc 284Thr Gly Leu Val Phe Cys Ser Leu Val Leu Gly Val Ser Ser Arg Ser5 10 15 20
ttc ttt tcg ttc ctt ggc gag gct ttt gat ggg gct cgg gac atg tgg 332Phe Phe Ser Phe Leu Gly Glu Ala Phe Asp Gly Ala Arg Asp Met Trp25 30 35aga gcc tac tct gac atg aga gaa gcc aat tac atc ggc tca gac aaa 380Arg Ala Tyr Ser Asp Met Arg Glu Ala Asn Tyr Ile Gly Ser Asp Lys40 45 50tac ttc cat gct cgg ggg aac tat gat gct gcc aaa agg gga cct ggg 428Tyr Phe His Ala Arg Gly Asn Tyr Asp Ala Ala Lys Arg Gly Pro Gly55 60 65ggt gcc tgg gct gca gaa gtg atc agc gat gcc aga gag aat atc cag 476Gly Ala Trp Ala Ala Glu Val Ile Ser Asp Ala Arg Glu Asn Ile Gln70 75 80aga ttc ttt ggc cat ggt gcg gag gac tcg ctg gct gat cag gct gcc 524Arg Phe Phe Gly His Gly Ala Glu Asp Ser Leu Ala Asp Gln Ala Ala85 90 95 100aat gaa tgg ggc agg agt ggc aaa gac ccc aat cac ttc cga cct gct 572Asn Glu Trp Gly Arg Ser Gly Lys Asp Pro Asn His Phe Arg Pro Ala105 110 115ggc ctg cct gag aaa tac tga gcttcctctt cactctgctc tcaggagatc 623Gly Leu Pro Glu Lys Tyr *120tggctgtgag gccctcaggg cagggataca aagcggggag agggtacaca atgggtatct 683aataaatact taagaggtgg aaaaaaaaaa aaaaaaaaa722<210>22<211>614<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(76)...(468)<400>22tatagctcca cggccagaag ataccagcag ctctgccttt actgaaattt cagctggaga 60aaggtccaca gcaca atg agg ctt ttc aca ggc att gtt ttc tgc tcc ttg 111
Met Arg Leu Phe Thr Gly Ile Val Phe Cys Ser Leu1 5 10gtc atg gga gtc acc agt gaa agc tgg cgt tcg ttt ttc aag gag gct 159Val Met Gly Val Thr Ser Glu Ser Trp Arg Ser Phe Phe Lys Glu Ala15 20 25ctc caa ggg gtt ggg gac atg ggc aga gcc tat tgg gac ata atg ata 207Leu Gln Gly Val Gly Asp Met Gly Arg Ala Tyr Trp Asp Ile Met Ile30 35 40tcc aat cac caa aat tca aac aga tat ctc tat gct cgg gga aac tat 255Ser Asn His Gln Asn Ser Asn Arg Tyr Leu Tyr Ala Arg Gly Asn Tyr45 50 55 60gat gct gcc caa aga gga cct ggg ggt gtc tgg gct gct aaa ctc atc 303Asp Ala Ala Gln Arg Gly Pro Gly Gly Val Trp Ala Ala Lys Leu Ile65 70 75agc cgt tcc agg gtc tat ctt cag gga tta ata gac tac tat tta ttt 351Ser Arg Ser Arg Val Tyr Leu Gln Gly Leu Ile Asp Tyr Tyr Leu Phe80 85 90gga aac agc agc act gta ttg gag gac tcg aag tcc aac gag aaa gct 399Gly Asn Ser Ser Thr Val Leu Glu Asp Ser Lys Ser Asn Glu Lys Ala95 100 105gag gaa tgg ggc cgg agt ggc aaa gac ccc gac cgc ttc aga cct gac 447Glu Glu Trp Gly Arg Ser Gly Lys Asp Pro Asp Arg Phe Arg Pro Asp110 115 120ggc ctg cct aag aaa tac tga gcttcctgct cctctgctct cagggaaact 498Gly Leu Pro Lys Lys Tyr *125 130gggctgtgag ccacacactt ctccccccag acagggacac agggtcactg agctttgtgt 558ccccaggaac tggtataggg cacctagagg tgttcaataa atgtttgtca aattga 614<210>23<211>874<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(94)...(702)<400>23gggcgggaag acgtgcagcc tgggccgtgg ctgctcactg cgttcggacc cagacccgct 60gcaggcagca gcagcccccg cccgcgcacg agc atg gag ctc tgg ggg gcc tac 114Met Glu Leu Trp Gly Ala Tyr1 5ctc ctc ctc tgc ctc ttc tcc ctc ctg acc cag gtc acc acc gag cca 162Leu Leu Leu Cys Leu Phe Ser Leu Leu Thr Gln Val Thr Thr Glu Pro10 15 20cca acc cag aag ccc aag aag att gta aat gcc aag aaa gat gtt gtg 210Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val25 30 35aac aca aag atg ttt gag gag ctc aag agc cgt ctg gac acc ctg gcc 258Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala40 45 50 55cag gag gtg gcc ctg ctg aag gag cag cag gcc ctg cag acg gtc tgc 306Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Cys60 65 70ctg aag ggg acc aag gtg cac atg aaa tgc ttt ctg gcc ttc acc cag 354Leu Lys Gly Thr Lys Val His Met Lys Cys Phe Leu Ala Phe Thr Gln75 80 85acg aag acc ttc cac gag gcc agc gag gac tgc atc tcg cgc ggg ggc 402Thr Lys Thr Phe His Glu Ala Ser Glu Asp Cys Ile Ser Arg Gly Gly90 95 100acc ctg agc acc cct cag act ggc tcg gag aac gac gcc ctg tat gag 450Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu Asn Asp Ala Leu Tyr Glu105 110 115tac ctg cgc cag agc gtg ggc aac gag gcc gag atc tgg ctg ggc ctc 498Tyr Leu Arg Gln Ser Val Gly Asn Glu Ala Glu Ile Trp Leu Gly Leu120 125 130 135aac gac atg gcg gcc gag ggc acc tgg gtg gac atg acc ggc gcc cgc 546Asn Asp Met Ala Ala Glu Gly Thr Trp Val Asp Met Thr Gly Ala Arg140 145 150
atc gcc tac aag aac tgg gag act gag atc acc gcg caa ccc gat ggc 594Ile Ala Tyr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro Asp Gly155 160 165ggc aag acc gag aac tgc gcg gtc ctg tca ggc gcg gcc aac ggc aag 642Gly Lys Thr Glu Asn Cys Ala Val Leu Ser Gly Ala Ala Asn Gly Lys170 175 180tgg ttc gac aag cgc tgc cgc gat cag ctg ccc tac atc tgc cag ttc 690Trp Phe Asp Lys Arg Cys Arg Asp Gln Leu Pro Tyr Ile Cys Gln Phe185 190 195ggg atc gtg tag ccggcggggc gggggccgtg gggggcctgg aggagggcag 742Gly Ile Val *200gagccgcggg aggccgggag gagggtgggg accttgcagc ccccatcctc tccgtgcgct 802tggagcctct ttttgcaaat aaagttggtg cacgttcgcg gagaggaaaa aaaaaaaaaa 862aaaaaaaaaa aa 874<210>24<211>615<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(27)...(470)<400>24acagaagtcc actcattctt ggcagg atg gct tct cat cgt ctg ctc ctc ctc 53Met Ala Ser His Arg Leu Leu Leu Leu1 5tgc ctt gct gga ctg gta ttt gtg tct gag gct ggc cct acg ggc acc 101Cys Leu Ala Gly Leu Val Phe Val Ser Glu Ala Gly Pro Thr Gly Thr10 15 20 25ggt gaa tcc aag tgt cct ctg atg gtc aaa gtt cta gat gct gtc cga 149Gly Glu Ser Lys Cys Pro Leu Met Val Lys Val Leu Asp Ala Val Arg30 35 40ggc agt cct gcc atc aat gtg gcc gtg cat gtg ttc aga aag gct gct 197
Gly Ser Pro Ala Ile Asn Val Ala Val His Val Phe Arg Lys Ala Ala45 50 55gat gac acc tgg gag cca ttt gcc tct ggg aaa acc agt gag tct gga 245Asp Asp Thr Trp Glu Pro Phe Ala Ser Gly Lys Thr Ser Glu Ser Gly60 65 70gag ctg cat ggg ctc aca act gag gag gaa ttt gta gaa ggg ata tac 293Glu Leu His Gly Leu Thr Thr Glu Glu Glu Phe Val Glu Gly Ile Tyr75 80 85aaa gtg gaa ata gac acc aaa tct tac tgg aag gca ctt ggc atc tcc 341Lys Val Glu Ile Asp Thr Lys Ser Tyr Trp Lys Ala Leu Gly Ile Ser90 95 100 105cca ttc cat gag cat gca gag gtg gta ttc aca gcc aac gac tcc ggc 389Pro Phe His Glu His Ala Glu Val Val Phe Thr Ala Asn Asp Ser Gly110 115 120ccc cgc cgc tac acc att gcc gcc ctg ctg agc ccc tac tcc tat tcc 437Pro Arg Arg Tyr Thr Ile Ala Ala Leu Leu Ser Pro Tyr Ser Tyr Ser125 130 135acc acg gct gtc gtc acc aat ccc aag gaa tga gggacttctc ctccagtgga 490Thr Thr Ala Val ValThr Asn Pro Lys Glu *140145cctgaaggac gagggatggg atttcatgta accaagagta ttccattttt actaaagcac 550tgttttcacc tcatatgcta tgttagaagt ccaggcagag acaataaaac attcctgtga 610aaggc 615<210>25<211>2022<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(494)...(1930)<400>25caatcatgga tcaatagcta tgtttggaga aggaatttgt ggctgctcca gctactgggc 60attttgtctg gtccagttca tgtaatctcc caacacccca tgaagcaagg ctttgttaat 120cctattttac tgaaaatgaa ctaagactca gagagataaa gctgttgccc aatgagcctt 180
ctttctgccc tccagatcca cggtgctaat tccccttccg atgacctaat gattctgagc 240ttggcaaagg tcttatctcc cagctcgccc aggcccagtg ttccaggaat gtgacctttg 300ctgcagcagc cgctggaggg ggcagagggg atgggctgga ggttgagcaa acagagcagc 360agaaaaggca gttcctcttc tccagtgccc tccttccctg tctctgcctc tccctccctt 420cctcaggcat cagagcggag acttcaggga gaccagagcc cagcttgcca ggcactgagc 480tagaagccct gcc atg gca ccc ctg aga ccc ctt ctc ata ctg gcc ctg529Met Ala Pro Leu Arg Pro Leu Leu Ile Leu Ala Leu1 5 10ctg gca tgg gtt gct ctg gct gac caa gag tca tgc aag ggc cgc tgc 577Leu Ala Trp Val Ala Leu Ala Asp Gln Glu Ser Cys Lys Gly Arg Cys15 20 25act gag ggc ttc aac gtg gac aag aag tgc cag tgt gac gag ctc tgc 625Thr Glu Gly Phe Asn Val Asp Lys Lys Cys Gln Cys Asp Glu Leu Cys30 35 40tct tac tac cag agc tgc tgc aca gac tat acg gct gag tgc aag ccc 673Ser Tyr Tyr Gln Ser Cys Cys Thr Asp Tyr Thr Ala Glu Cys Lys Pro45 50 55 60caa gtg act cgc ggg gat gtg ttc act atg ccg gag gat gag tac acg 721Gln Val Thr Arg Gly Asp Val Phe Thr Met Pro Glu Asp Glu Tyr Thr65 70 75gtc tat gac gat ggc gag gag aaa aac aat gcc act gtc cat gaa cag 769Val Tyr Asp Asp Gly Glu Glu Lys Asn Asn Ala Thr Val His Glu Gln80 85 90gtg ggg ggc ccc tcc ctg acc tct gac ctc cag gcc cag tcc aaa ggg 817Val Gly Gly Pro Ser Leu Thr Ser Asp Leu Gln Ala Gln Ser Lys Gly95 100 105aat cct gag cag aca cct gtt ctg aaa cct gag gaa gag gcc cct gcg 865Asn Pro Glu Gln Thr Pro Val Leu Lys Pro Glu Glu Glu Ala Pro Ala110 115 120cct gag gtg ggc gcc tct aag cct gag ggg ata gac tca agg cct gag 913Pro Glu Val Gly Ala Ser Lys Pro Glu Gly Ile Asp Ser Arg Pro Glu125 130 135 140acc ctt cat cca ggg aga cct cag ccc cca gca gag gag gag ctg tgc 961Thr Leu His Pro Gly Arg Pro Gln Pro Pro Ala Glu Glu Glu Leu Cys145 150 155
agt ggg aag ccc ttc gac gcc ttc acc gac ctc aag aac ggt tcc ctc 1009Ser Gly Lys Pro Phe Asp Ala Phe Thr Asp Leu Lys Asn Gly Ser Leu160 165 170ttt gcc ttc cga ggg cag tac tgc tat gaa ctg gac gaa aag gca gtg 1057Phe Ala Phe Arg Gly Gln Tyr Cys Tyr Glu Leu Asp Glu Lys Ala Val175 180 185agg cct ggg tac ccc aag ctc atc cga gat gtc tgg ggc atc gag ggc 1105Arg Pro Gly Tyr Pro Lys Leu Ile Arg Asp Val Trp Gly Ile Glu Gly190 195 200ccc atc gat gcc gcc ttc acc cgc atc aac tgt cag ggg aag acc tac 1153Pro Ile Asp Ala Ala Phe Thr Arg Ile Asn Cys Gln Gly Lys Thr Tyr205 210 215 220ctc ttc aag ggt agt cag tac tgg cgc ttt gag gat ggt gtc ctg gac 1201Leu Phe Lys Gly Ser Gln Tyr Trp Arg Phe Glu Asp Gly Val Leu Asp225 230 235cct gat tac ccc cga aat atc tct gac ggc ttc gat ggc atc ccg gac 1249Pro Asp Tyr Pro Arg Asn Ile Ser Asp Gly Phe Asp Gly Ile Pro Asp240 245 250aac gtg gat gca gcc ttg gcc ctc cct gcc cat agc tac agt ggc cgg 1297Asn Val Asp Ala Ala Leu Ala Leu Pro Ala His Ser Tyr Ser Gly Arg255 260 265gag cgg gtc tac ttc ttc aag ggg aaa cag tac tgg gag tac cag ttc 1345Glu Arg Val Tyr Phe Phe Lys Gly Lys Gln Tyr Trp Glu Tyr Gln Phe270 275 280cag cac cag ccc agt cag gag gag tgt gaa ggc agc tcc ctg tcg gct 1393Gln His Gln Pro Ser Gln Glu Glu Cys Glu Gly Ser Ser Leu Ser Ala285 290 295 300gtg ttt gaa cac ttt gcc atg atg cag cgg gac agc tgg gag gac atc 1441Val Phe Glu His Phe Ala Met Met Gln Arg Asp Ser Trp Glu Asp Ile305 310 315ttc gag ctt ctc ttc tgg ggc aga acc tct gct ggt acc aga cag ccc 1489Phe Glu Leu Leu Phe Trp Gly Arg Thr Ser Ala Gly Thr Arg Gln Pro320 325 330
cag ttc att agc cgg gac tgg cac ggt gtg cca ggg caa gtg gac gca 1537Gln Phe Ile Ser Arg Asp Trp His Gly Val Pro Gly Gln Val Asp Ala335 340345gcc atg gct ggc cgc atc tac atc tca ggc atg gca ccc cgc ccc tcc 1585Ala Met Ala Gly Arg Ile Tyr Ile Ser Gly Met Ala Pro Arg Pro Ser350 355 360ttg gcc aag aaa caa agg ttt agg cat cgc aac cgc aaa ggc tac cgt 1633Leu Ala Lys Lys Gln Arg Phe Arg His Arg Asn Arg Lys Gly Tyr Arg365 370 375 380tca caa cga ggc cac agc cgt ggc cgc aac cag aac tcc cgc cgg cca 1681Ser Gln Arg Gly His Ser Arg Gly Arg Asn Gln Asn Ser Arg Arg Pro385 390 395tcc cgc gcc atg tgg ctg tcc ttg ttc tcc agt gag gag agc aac ttg 1729Ser Arg Ala Met Trp Leu Ser Leu Phe Ser Ser Glu Glu Ser Asn Leu400 405 410gga gcc aac aac tat gat gac tac agg atg gac tgg ctt gtg cct gcc 1777Gly Ala Asn Asn Tyr Asp Asp Tyr Arg Met Asp Trp Leu Val Pro Ala415 420 425acc tgt gaa ccc atc cag agt gtc ttc ttc ttc tct gga gac aag tac 1825Thr Cys Glu Pro Ile Gln Ser Val Phe Phe Phe Ser Gly Asp Lys Tyr430 435 440tac cga gtc aat ctt cgc aca cgg cga gtg gac act gtg gac cct ccc 1873Tyr Arg Val Asn Leu Arg Thr Arg Arg Val Asp Thr Val Asp Pro Pro445 450 455 460tac cca cgc tcc atc gct cag tac tgg ctg ggc tgc cca gct cct ggc 1921Tyr Pro Arg Ser Ile Ala Gln Tyr Trp Leu Gly Cys Pro Ala Pro Gly465 470 475cat ctg tag gagtcagagc ccacatggcc gggccctctg tagctccctc 1970His Leu *ctcccatctc cttcccccag cccaataaag gtcccttagc cccgagttta aa 2022<210>26
<211>1166<212>DNA<213>人類(lèi)<220>
<221>CDS<222>(7)...(894)<400>26gcaaga atg gtg cct gtc ctg ctg tct ctg ctg ctg ctt ctg ggt cct48Met Val Pro Val Leu Leu Ser Leu Leu Leu Leu Leu Gly Pro1 5 10gct gtc ccc cag gag aac caa gat ggt cgt tac tct ctg acc tat atc 96Ala Val Pro Gln Glu Asn Gln Asp Gly Arg Tyr Ser Leu Thr Tyr Ile15 20 25 30tac act ggg ctg tcc aag cat gtt gaa gac gtc ccc gcg ttt cag gcc 144Tyr Thr Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln Ala35 40 45ctt ggc tca ctc aat gac ctc cag ttc ttt aga tac aac agt aaa gac 192Leu Gly Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys Asp50 55 60agg aag tct cag ccc atg gga ctc tgg aga cag gtg gaa gga atg gag 240Arg Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met Glu65 70 75gat tgg aag cag gac agc caa ctt cag aag gcc agg gag gac atc ttt 288Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile Phe80 85 90atg gag acc ctg aaa gac att gtg gag tat tac aac gac agt aac ggg 336Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser Asn Gly95 100 105 110tct cac gta ttg cag gga agg ttt ggt tgt gag atc gag aat aac aga 384Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile Glu Asn Asn Arg115 120 125agc agc gga gca ttc tgg aaa tat tac tat gat gga aag gac tac att 432Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly Lys Asp Tyr Ile130 135 140
gaa ttc aac aaa gaa atc cca gcc tgg gtc ccc ttc gac cca gca gcc480Glu Phe Asn Lys Glu Ile Pro Ala Trp Val Pro Phe Asp Pro Ala Ala145 150 155cag ata acc aag cag aag tgg gag gca gaa cca gtc tac gtg cag cgg528Gln Ile Thr Lys Gln Lys Trp Glu Ala Glu Pro Val Tyr Val Gln Arg160 165 170gcc aag gct tac ctg gag gag gag tgc cct gcg act ctg cgg aaa tac576Ala Lys Ala Tyr Leu Glu Glu Glu Cys Pro Ala Thr Leu Arg Lys Tyr175 180 185 190ctg aaa tac agc aaa aat atc ctg gac cgg caa gat cct ccc tct gtg624Leu Lys Tyr Ser Lys Asn Ile Leu Asp Arg Gln Asp Pro Pro Ser Val195 200 205gtg gtc acc agc cac cag gcc cca gga gaa aag aag aaa ctg aag tgc672Val Val Thr Ser His Gln Ala Pro Gly Glu Lys Lys Lys Leu Lys Cys210 215 220ctg gcc tac gac ttc tac cca ggg aaa att gat gtg cac tgg act cgg720Leu Ala Tyr Asp Phe Tyr Pro Gly Lys Ile Asp Val His Trp Thr Arg225 230 235gcc ggc gag gtg cag gag cct gag tta cgg gga gat gtt ctt cac aat768Ala Gly Glu Val Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His Asn240245 250gga aat ggc act tac cag tcc tgg gtg gtg gtg gca gtg ccc ccg cag816Gly Asn Gly Thr Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro Gln255 260 265 270gac aca gcc ccc tac tcc tgc cac gtg cag cac agc agc ctg gcc cag864Asp Thr Ala Pro Tyr Ser Cys His Val Gln His Ser Ser Leu Ala Gln275 280 285ccc ctc gtg gtg ccc tgg gag gcc agc tag gaagcaaggg ttggaggcaa 914Pro Leu Val Val Pro Trp Glu Ala Ser *290 295tgtgggatct cagacccagt agctgccctt cctgcctgat gtgggagctg aaccacagaa 974atcacagtca atggatccac aaggcctgag gagcagtgtg gggggacaga caggaggtgg 1034atttggagac cgaagactgg gatgcctgtc ttgagtagac ttggacccaa aaaatcatct 1094
caccttgagc ccacccccac cccattgtct aatctgtaga agctaataaa taatcatccc 1154tccttgccta gc 1166<210>27<211>418<212>PRT<213>人類(lèi)<400>27Met Pro Ser Ser Val Ser Trp Gly Ile Leu Leu Leu Ala Gly Leu Cys1 5 10 15Cys Leu Val Pro Val Ser Leu Ala Glu Asp Pro Gln Gly Asp Ala Ala20 25 30Gln Lys Thr Asp Thr Ser His His Asp Gln Asp His Pro Thr Phe Asn35 40 45Lys Ile Thr Pro Asn Leu Ala Glu Phe Ala Phe Ser Leu Tyr Arg Gln50 55 60Leu Ala His Gln Ser Asn Ser Thr Asn Ile Phe Phe Ser Pro Val Ser65 70 75 80Ile Ala Thr Ala Phe Ala Met Leu Ser Leu Gly Thr Lys Ala Asp Thr85 90 95His Asp Glu Ile Leu Glu Gly Leu Asn Phe Asn Leu Thr Glu Ile Pro100 105 110Glu Ala Gln Ile His Glu Gly Phe Gln Glu Leu Leu Arg Thr Leu Asn115 120 125Gln Pro Asp Ser Gln Leu Gln Leu Thr Thr Gly Asn Gly Leu Phe Leu130 135 140Ser Glu Gly Leu Lys Leu Val Asp Lys Phe Leu Glu Asp Val Lys Lys145 150 155 160Leu Tyr His Ser Glu Ala Phe Thr Val Asn Phe Gly Asp Thr Glu Glu165 170 175Ala Lys Lys Gln Ile Asn Asp Tyr Val Glu Lys Gly Thr Gln Gly Lys180 185 190Ile Val Asp Leu Val Lys Glu Leu Asp Arg Asp Thr Val Phe Ala Leu195 200 205Val Asn Tyr Ile Phe Phe Lys Gly Lys Trp Glu Arg Pro Phe Glu Val210 215 220Lys Asp Thr Glu Glu Glu Asp Phe His Val Asp Gln Val Thr Thr Val225 230 235 240Lys Val Pro Met Met Lys Arg Leu Gly Met Phe Asn Ile Gln His Cys245 250 255Lys Lys Leu Ser Ser Trp Val Leu Leu Met Lys Tyr Leu Gly Asn Ala260 265 270Thr Ala Ile Phe Phe Leu Pro Asp Glu Gly Lys Leu Gln His Leu Glu
275 280 285Asn Glu Leu Thr His Asp Ile Ile Thr Lys Phe Leu Glu Asn Glu Asp290 295 300Arg Arg Ser Ala Ser Leu His Leu Pro Lys Leu Ser Ile Thr Gly Thr305 310 315 320Tyr Asp Leu Lys Ser Val Leu Gly Gln Leu Gly Ile Thr Lys Val Phe325 330 335Ser Asn Gly Ala Asp Leu Ser Gly Val Thr Glu Glu Ala Pro Leu Lys340 345 350Leu Ser Lys Ala Val His Lys Ala Val Leu Thr Ile Asp Glu Lys Gly355 360 365Thr Glu Ala Ala Gly Ala Met Phe Leu Glu Ala Ile Pro Met Ser Ile370 375 380Pro Pro Glu Val Lys Phe Asn Lys Pro Phe Val Phe Leu Met Ile Glu385 390 395 400Gln Asn Thr Lys Ser Pro Leu Phe Met Gly Lys Val Val Asn Pro Thr405 410 415Gln Lys<210>28<211>352<212>PRT<213>人類(lèi)<400>28Met Arg Ser Leu Gly Ala Leu Leu Leu Leu Leu Ser Ala Cys Leu Ala1 5 10 15Val Ser Ala Gly Pro Val Pro Thr Pro Pro Asp Asn Ile Gln Val Gln20 25 30Glu Asn Phe Asn Ile Ser Arg Ile Tyr Gly Lys Trp Tyr Asn Leu Ala35 40 45Ile Gly Ser Thr Cys Pro Trp Leu Lys Lys Ile Met Asp Arg Met Thr50 55 60Val Ser Thr Leu Val Leu Gly Glu Gly Ala Thr Glu Ala Glu Ile Ser65 70 75 80Met Thr Ser Thr Arg Trp Arg Lys Gly Val Cys Glu Glu Thr Ser Gly85 90 95Ala Tyr Glu Lys Thr Asp Thr Asp Gly Lys Phe Leu Tyr His Lys Ser100 105 110Lys Trp Asn Ile Thr Met Glu Ser Tyr Val Val His Thr Asn Tyr Asp115 120 125Glu Tyr Ala Ile Phe Leu Thr Lys Lys Phe Ser Arg His His Gly Pro
130 135 140Thr Ile Thr Ala Lys Leu Tyr Gly Arg Ala Pro Gln Leu Arg Glu Thr145 150 155 160Leu Leu Gln Asp Phe Arg Val Val Ala Gln Gly Val Gly Ile Pro Glu165 170 175Asp Ser Ile Phe Thr Met Ala Asp Arg Gly Glu Cys Val Pro Gly Glu180 185 190Gln Glu Pro Glu Pro Ile Leu Ile Pro Arg Val Arg Arg Ala Val Leu195 200 205Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val Thr Glu Val210 215 220Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala Gly Pro Cys225 230 235 240Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser Met Ala Cys245 250 255Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn Asn Phe Val260 265 270Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala Ala Cys Asn275 280 285Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln Leu Trp Ala290 295 300Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr Gly Gly Cys305 310 315 320Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr325 330 335Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg Phe Ser Asn340 345 350<210>29<211>398<212>PRT<213>人類(lèi)<400>29Met Glu Gly Ala Ala Leu Leu Arg Val Ser Val Leu Cys Ile Trp Met1 5 10 15Ser Ala Leu Phe Leu Gly Val Arg Val Arg Ala Glu Glu Ala Gly Ala20 25 30Arg Val Gln Gln Asn Val Pro Ser Gly Thr Asp Thr Gly Asp Pro Gln35 40 45Ser Lys Pro Leu Gly Asp Trp Ala Ala Gly Thr Met Asp Pro Glu Ser50 55 60Ser Ile Phe Ile Glu Asp Ala Ile Lys Tyr Phe Lys Glu Lys Val Ser
65 70 75 80Thr Gln Asn Leu Leu Leu Leu Leu Thr Asp Asn Glu Ala Trp Asn Gly85 90 95Phe Val Ala Ala Ala Glu Leu Pro Arg Asn Glu Ala Asp Glu Leu Arg100 105 110Lys Ala Leu Asp Asn Leu Ala Arg Gln Met Ile Met Lys Asp Lys Asn115 120 125Trp His Asp Lys Gly Gln Gln Tyr Arg Asn Trp Phe Leu Lys Glu Phe130 135 140Pro Arg Leu Lys Ser Lys Leu Glu Asp Asn Ile Arg Arg Leu Arg Ala145 150 155 160Leu Ala Asp Gly Val Gln Lys Val His Lys Gly Thr Thr Ile Ala Asn165 170 175Val Val Ser Gly Ser Leu Ser Ile Ser Ser Gly Ile Leu Thr Leu Val180 185 190Gly Met Gly Leu Ala Pro Phe Thr Glu Gly Gly Ser Leu Val Leu Leu195 200 205Glu Pro Gly Met Glu Leu Gly Ile Thr Ala Ala Leu Thr Gly Ile Thr210 215 220Ser Ser Thr Ile Asp Tyr Gly Lys Lys Trp Trp Thr Gln Ala Gln Ala225 230 235 240His Asp Leu Val Ile Lys Ser Leu Asp Lys Leu Lys Glu Val Lys Glu245 250 255Phe Leu Gly Glu Asn Ile Ser Asn Phe Leu Ser Leu Ala Gly Asn Thr260 265 270Tyr Gln Leu Thr Arg Gly Ile Gly Lys Asp Ile Arg Ala Leu Arg Arg275 280 285Ala Arg Ala Asn Leu Gln Ser Val Pro His Ala Ser Ala Ser Arg Pro290 295 300Arg Val Thr Glu Pro Ile Ser Ala Glu Ser Gly Glu GIn Val Glu Arg305 310 315 320Val Asn Glu Pro Ser Ile Leu Glu Met Ser Arg Gly Val Lys Leu Thr325 330 335Asp Val Ala Pro Val Ser Phe Phe Leu Val Leu Asp Val Val Tyr Leu340 345 350Val Tyr Glu Ser Lys His Leu His Glu Gly Ala Lys Ser Glu Thr Ala355 360 365Glu Glu Leu Lys Lys Val Ala Gln Glu Leu Glu Glu Lys Leu Asn Ile370 375 380Leu Asn Asn Asn Tyr Lys Ile Leu Gln Ala Asp Gln Glu Leu385 390 395<210>30
<211>114<212>PRT<213>人類(lèi)<400>30Met Thr Cys Lys Met Ser Gln Leu Glu Arg Asn Ile Glu Thr Ile Ile1 5 10 15Asn Thr Phe His Gln Tyr Ser Val Lys Leu Gly His Pro Asp Thr Leu20 25 30Asn Gln Gly Glu Phe Lys Glu Leu Val Arg Lys Asp Leu Gln Asn Phe35 40 45Leu Lys Lys Glu Asn Lys Asn Glu Lys Val Ile Glu His Ile Met Glu50 55 60Asp Leu Asp Thr Asn Ala Asp Lys Gln Leu Ser Phe Glu Glu Phe Ile65 70 75 80Met Leu Met Ala Arg Leu Thr Trp Ala Ser His Glu Lys Met His Glu85 90 95Gly Asp Glu Gly Pro Gly His His His Lys Pro Gly Leu Gly Glu Gly100 105 110Thr Pro<210>31<211>261<212>PRT<213>人類(lèi)<400>31Met Ala Ser Pro Asp Trp Gly Tyr Asp Asp Lys Asn Gly Pro Glu Gln1 5 10 15Trp Ser Lys Leu Tyr Pro Ile Ala Asn Gly Asn Asn Gln Ser Pro Val20 25 30Asp Ile Lys Thr Ser Glu Thr Lys His Asp Thr Ser Leu Lys Pro Ile35 40 45Ser Val Ser Tyr Asn Pro Ala Thr Ala Lys Glu Ile Ile Asn Val Gly50 55 60His Ser Phe His Val Asn Phe Glu Asp Asn Asp Asn Arg Ser Val Leu65 70 75 80Lys Gly Gly Pro Phe Ser Asp Ser Tyr Arg Leu Phe Gln Phe His Phe85 90 95His Trp Gly Ser Thr Asn Glu His Gly Ser Glu His Thr Val Asp Gly100 105 110Val Lys Tyr Ser Ala Glu Leu His Val Ala His Trp Asn Ser Ala Lys
115 120 125Tyr Ser Ser Leu Ala Glu Ala Ala Ser Lys Ala Asp Gly Leu Ala Val130 135 140Ile Gly Val Leu Met Lys Val Gly Glu Ala Asn Pro Lys Leu Gln Lys145 150 155 160Val Leu Asp Ala Leu Gln Ala Ile Lys Thr Lys Gly Lys Arg Ala Pro165 170175Phe Thr Asn Phe Asp Pro Ser Thr Leu Leu Pro Ser Ser Leu Asp Phe180 185 190Trp Thr Tyr Pro Gly Ser Leu Thr His Pro Pro Leu Tyr Glu Ser Val195 200 205Thr Trp Ile Ile Cys Lys Glu Ser Ile Ser Val Ser Ser Glu Gln Leu210 215 220AIa Gln Phe Arg Ser Leu Leu Ser Asn Val Glu Gly Asp Asn Ala Val225 230 235 240Pro Met Gln His Asn Asn Arg Pro Thr Gln Pro Leu Lys Gly Arg Thr245 250 255Val Arg Ala Ser Phe260<210>32<211>449<212>PRT<213>人類(lèi)<400>32Met Met Lys Thr Leu Leu Leu Phe Val Gly Leu Leu Leu Thr Trp Glu1 5 10 15Ser Gly Gln Val Leu Gly Asp Gln Thr Val Ser Asp Asn Glu Leu Gln20 25 30Glu Met Ser Asn Gln Gly Ser Lys Tyr Val Asn Lys Glu Ile Gln Asn35 40 45Ala Val Asn Gly Val Lys Gln Ile Lys Thr Leu Ile Glu Lys Thr Asn50 55 60Glu Glu Arg Lys Thr Leu Leu Ser Asn Leu Glu Glu Ala Lys Lys Lys65 70 75 80Lys Glu Asp Ala Leu Asn Glu Thr Arg Glu Ser Glu Thr Lys Leu Lys85 90 95Glu Leu Pro Gly Val Cys Asn Glu Thr Met Met Ala Leu Trp Glu Glu100 105 110Cys Lys Pro Cys Leu Lys Gln Thr Cys Met Lys Phe Tyr Ala Arg Val115 120 125Cys Arg Ser Gly Ser Gly Leu Val Gly Arg Gln Leu Glu Glu Phe Leu
130 135 140Asn Gln Ser Ser Pro Phe Tyr Phe Trp Met Asn Gly Asp Arg Ile Asp145 150 155 160Ser Leu Leu Glu Asn Asp Arg Gln Gln Thr His Met Leu Asp Val Met165 170 175Gln Asp His Phe Ser Arg Ala Ser Ser Ile Ile Asp Glu Leu Phe Gln180 185 190Asp Arg Phe Phe Thr Arg Glu Pro Gln Asp Thr Tyr His Tyr Leu Pro195 200 205Phe Ser Leu Pro His Arg Arg Pro His Phe Phe Phe Pro Lys Ser Arg210 215 220Ile Val Arg Ser Leu Met Pro Phe Ser Pro Tyr Glu Pro Leu Asn Phe225 230 235 240His Ala Met Phe Gln Pro Phe Leu Glu Met Ile His Glu Ala Gln Gln245 250 255Ala Met Asp Ile His Phe His Ser Pro Ala Phe Gln His Pro Pro Thr260 265 270Glu Phe Ile Arg Glu Gly Asp Asp Asp Arg Thr Val Cys Arg Glu Ile275 280 285Arg His Asn Ser Thr Gly Cys Leu Arg Met Lys Asp Gln Cys Asp Lys290 295 300Cys Arg Glu Ile Leu Ser Val Asp Cys Ser Thr Asn Asn Pro Ser Gln305 310 315 320Ala Lys Leu Arg Arg Glu Leu Asp Glu Ser Leu Gln Val Ala Glu Arg325 330 335Leu Thr Arg Lys Tyr Asn Glu Leu Leu Lys Ser Tyr Gln Trp Lys Met340 345 350Leu Asn Thr Ser Ser Leu Leu Glu Gln Leu Asn Glu Gln Phe Asn Trp355 360 365Val Ser Arg Leu Ala Asn Leu Thr Gln Gly Glu Asp Gln Tyr Tyr Leu370 375 380Arg Val Thr Thr Val Ala Ser His Thr Ser Asp Ser Asp Val Pro Ser385 390 395 400Gly Val Thr Glu Val Val Val Lys Leu Phe Asp Ser Asp Pro Ile Thr405 410 415Val Thr Val Pro Val Glu Val Ser Arg Lys Asn Pro Lys Phe Met Glu420 425 430Thr Val Ala Glu Lys Ala Leu Gln Glu Tyr Arg Lys Lys His Arg Glu435 440 445Glu<210>33
<211>166<212>PRT<213>人類(lèi)<400>33Met Ala Ser Gly Val Ala Val Ser Asp Gly Val Ile Lys Val Phe Asn1 5 10 15Asp Met Lys Val Arg Lys Ser Ser Thr Pro Glu Glu Val Lys Lys Arg20 25 30Lys Lys Ala Val Leu Phe Cys Leu Ser Glu Asp Lys Lys Asn Ile Ile35 40 45Leu Glu Glu Gly Lys Glu Ile Leu Val Gly Asp Val Gly Gln Thr Val50 55 60Asp Asp Pro Tyr Ala Thr Phe Val Lys Met Leu Pro Asp Lys Asp Cys65 70 75 80Arg Tyr Ala Leu Tyr Asp Ala Thr Tyr Glu Thr Lys Glu Ser Lys Lys85 90 95Glu Asp Leu Val Phe Ile Phe Trp Ala Pro Glu Ser Ala Pro Leu Lys100 105 110Ser Lys Met Ile Tyr Ala Ser Ser Lys Asp Ala Ile Lys Lys Lys Leu115 120 125Thr Gly Ile Lys His Glu Leu Gln Ala Asn Cys Tyr Glu Glu Val Lys130 135 140Asp Arg Cys Thr Leu Ala Glu Lys Leu Gly Gly Ser Ala Val Ile Ser145 150 155 160Leu Glu Gly Lys Pro Leu165<210>34<211>1663<212>PRT<213>人類(lèi)<400>34Met Gly Pro Thr Ser Gly Pro Ser Leu Leu Leu Leu Leu Leu Thr His1 5 10 15Leu Pro Leu Ala Leu Gly Ser Pro Met Tyr Ser Ile Ile Thr Pro Asn20 25 30Ile Leu Arg Leu Glu Ser Glu Glu Thr Met Val Leu Glu Ala His Asp35 40 45Ala Gln Gly Asp Val Pro Val Thr Val Thr Val His Asp Phe Pro Gly50 55 60Lys Lys Leu Val Leu Ser Ser Glu Lys Thr Val Leu Thr Pro Ala Thr
65 70 75 80Asn His Met Gly Asn Val Thr Phe Thr Ile Pro Ala Asn Arg Glu Phe85 90 95Lys Ser Glu Lys Gly Arg Asn Lys Phe ValThr Val Gln Ala Thr Phe100 105110Gly Thr Gln Val Val Glu Lys Val Val Leu Val Ser Leu Gln Ser Gly115 120 125Tyr Leu Phe Ile Gln Thr Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr130 135 140Val Leu Tyr Arg Ile Phe Thr Val Asn His Lys Leu Leu Pro Val Gly145 150 155 160Arg Thr Val Met Val Asn Ile Glu Asn Pro Glu Gly Ile Pro Val Lys165 170 175Gln Asp Ser Leu Ser Ser Gln Asn Gln Leu Gly Val Leu Pro Leu Ser180 185 190Trp Asp Ile Pro Glu Leu Val Asn Met Gly Gln Trp Lys Ile Arg Ala195 200 205Tyr Tyr Glu Asn Ser Pro Gln Gln Val Phe Ser Thr Glu Phe Glu Val210 215 220Lys Glu Tyr Val Leu Pro Ser Phe Glu Val Ile Val Glu Pro Thr Glu225 230 235 240Lys Phe Tyr Tyr Ile Tyr Asn Glu Lys Gly Leu Glu Val Thr Ile Thr245 250 255Ala Arg Phe Leu Tyr Gly Lys Lys Val Glu Gly Thr Ala Phe Val Ile260 265 270Phe Gly Ile Gln Asp Gly Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu275 280 285Lys Arg Ile Pro Ile Glu Asp Gly Ser Gly Glu Val Val Leu Ser Arg290 295 300Lys Val Leu Leu Asp Gly Val Gln Asn Leu Arg Ala Glu Asp Leu Val305 310 315 320Gly Lys Ser Leu Tyr Val Ser Ala Thr Val Ile Leu His Ser Gly Ser325 330 335Asp Met Val Gln Ala Glu Arg Ser Gly Ile Pro Ile Val Thr Ser Pro340 345 350Tyr Gln Ile His Phe Thr Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met355 360 365Pro Phe Asp Leu Met Val Phe Val Thr Asn Pro Asp Gly Ser Pro Ala370 375 380Tyr Arg Val Pro Val Ala Val Gln Gly Glu Asp Thr Val Gln Ser Leu385 390 395 400Thr Gln Gly Asp Gly Val Ala Lys Leu Ser Ile Asn Thr His Pro Ser405 410 415Gln Lys Pro Leu Ser Ile Thr Val Arg Thr Lys Lys Gln Glu Leu Ser
420 425 430Glu Ala Glu Gln Ala Thr Arg Thr Met Gln Ala Leu Pro Tyr Ser Thr435 440 445Val Gly Asn Ser Asn Asn Tyr Leu His Leu Ser Val Leu Arg Thr Glu450 455 460Leu Arg Pro Gly Glu Thr Leu Asn Val Asn Phe Leu Leu Arg Met Asp465 470 475 480Arg Ala His Glu Ala Lys Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn485 490 495Lys Gly Arg Leu Leu Lys Ala Gly Arg Gln Val Arg Glu Pro Gly Gln500 505 510Asp Leu Val Val Leu Pro Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser515 520 525Phe Arg Leu Val Ala Tyr Tyr Thr Leu Ile Gly Ala Ser Gly Gln Arg530 535 540Glu Val Val Ala Asp Ser Val Trp Val Asp Val Lys Asp Ser Cys Val545 550 555 560Gly Ser Leu Val Val Lys Ser Gly Gln Ser Glu Asp Arg Gln Pro Val565 570 575Pro Gly Gln Gln Met Thr Leu Lys Ile Glu Gly Asp His Gly Ala Arg580 585 590Val Val Leu Val Ala Val Asp Lys Gly Val Phe Val Leu Asn Lys Lys595 600 605Asn Lys Leu Thr Gln Ser Lys Ile Trp Asp Val Val Glu Lys Ala Asp610 615 620Ile Gly Cys Thr Pro Gly Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser625 630 635 640Asp Ala Gly Leu Thr Phe Thr Ser Ser Ser Gly Gln Gln Thr Ala Gln645 650 655Arg Ala Glu Leu Gln Cys Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser660 665 670Val Gln Leu Thr Glu Lys Arg Met Asp Lys Val Gly Lys Tyr Pro Lys675 680 685Glu Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Glu Asn Pro Met Arg690 695 700Phe Ser Cys Gln Arg Arg Thr Arg Phe Ile Ser Leu Gly Glu Ala Cys705 710 715 720Lys Lys Val Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg725 730 735Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg Ser Asn Leu Asp740 745 750Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg Ser Glu Phe Pro755 760 765Glu Ser Trp Leu Trp Asn Val Glu Asp Leu Lys Glu Pro Pro Lys Asn
770 775 780Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys Asp Ser Ile Thr785 790 795 800Thr Trp Glu Ile Leu Ala Val Ser Met Ser Asp Lys Lys Gly Ile Cys805 810 815Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp Phe Phe Ile Asp820 825 830Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile Arg835 840 845Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu Lys Val Arg Val850 855 860Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala Thr Thr Lys Arg865 870 875 880Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser Ser Leu Ser Val885 890 895Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Leu Gln Glu Val Glu Val900 905 910Lys Ala Ala ValTyr His His Phe Ile Ser Asp Gly Val Arg Lys Ser915920 925Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys Thr Val Ala Val930 935 940Arg Thr Leu Asp Pro Glu Arg Leu Gly Arg Glu Gly Val Gln Lys Glu945 950 955 960Asp Ile Pro Pro Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Glu Ser965 970 975Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Thr Glu980 985 990Asp Ala Val Asp Ala Glu Arg Leu Lys His Leu Ile Val Thr Pro Ser995 10001005Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro Thr Val Ile Ala101010151020Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys Phe Gly Leu Glu102510301035 1040Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly Tyr Thr Gln Gln104510501055Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala Phe Val Lys Arg106010651070Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val Lys Val Phe Ser Leu107510801085Ala Val Asn Leu Ile Ala Ile Asp Ser Gln Val Leu Cys Gly Ala Val109010951100Lys Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly Val Phe Gln Glu110511101115 1120Asp Ala Pro Val Ile His Gln Glu Met Ile Gly Gly Leu Arg Asn Asn
112511301135Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu Ile Ser Leu Gln114011451150Glu Ala Lys Asp Ile Cys Glu Glu Gln Val Asn Ser Leu Pro Gly Ser115511601165Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr Met Asn Leu Gln117011751180Arg Ser Tyr Thr Val Ala Ile Ala Gly Tyr Ala Leu Ala Gln Met Gly118511901195 1200Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe Leu Thr Thr Ala Lys Asp120512101215Lys Asn Arg Trp Glu Asp Pro Gly Lys Gln Leu Tyr Asn Val Glu Ala122012251230Thr Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys Asp Phe Asp Phe123512401245Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg Tyr Tyr Gly Gly125012551260Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala Leu Ala126512701275 1280Gln Tyr Gln Lys Asp Ala Pro Asp His Gln Glu Leu Asn Leu Asp Val128512901295Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Thr His Arg Ile His130013051310Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu Thr Lys Glu Asn Glu131513201325Gly Phe Thr Val Thr Ala Glu Gly Lys Gly Gln Gly Thr Leu Ser Val133013351340Val Thr Met Tyr His Ala Lys Ala Lys Asp Gln Leu Thr Cys Asn Lys134513501355 1360Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu Thr Glu Lys Arg136513701375Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile Cys Thr Arg Tyr138013851390Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp Ile Ser Met Met139514001405Thr Gly Phe Ala Pro Asp Thr Asp Asp Leu Lys Gln Leu Ala Asn Gly141014151420Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp Lys Ala Phe Ser Asp142514301435 1440Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys Val Ser His Ser Glu Asp144514501455Asp Cys Leu Ala Phe Lys Val His Gln Tyr Phe Asn Val Glu Leu Ile146014651470Gln Pro Gly Ala Val Lys ValTyr Ala Tyr Tyr Asn Leu Glu Glu Ser
147514801485Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly Lys Leu Asn Lys149014951500Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu Asn Cys Phe Ile150515101515 1520Gln Lys Ser Asp Asp Lys Val Thr Leu Glu Glu Arg Leu Asp Lys Ala152515301535Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg Leu Val Lys Val154015451550Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met Ala Ile Glu Gln Thr155515601565Ile Lys Ser Gly Ser Asp Glu Val Gln Val Gly Gln Gln Arg Thr Phe157015751580Ile Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu Glu Glu Lys Lys158515901595 1600His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp Gly Glu Lys Pro160516101615Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val Glu His Trp Pro162016251630Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys Gln Cys Gln Asp163516401645Leu Gly Ala Phe Thr Glu Ser Met Val Val Phe Gly Cys Pro Asn165016551660<210>35<211>270<212>PRT<213>人類(lèi)<400>35Met Trp Leu Leu Val Ser Val Ile Leu Ile Ser Arg Ile Ser Ser Val1 5 10 15Gly Gly Glu Ala Met Phe Cys Asp Phe Pro Lys Ile Asn His Gly Ile20 25 30Leu Tyr Asp Glu Glu Lys Tyr Lys Pro Phe Ser Gln Val Pro Thr Gly35 40 45Glu Val Phe Tyr Tyr Ser Cys Glu Tyr Asn Phe Val Ser Pro Ser Lys50 55 60Ser Phe Trp Thr Arg Ile Thr Cys Ala Glu Glu Gly Trp Ser Pro Thr65 70 75 80Pro Lys Cys Leu Arg Leu Cys Phe Phe Pro Phe Val Glu Asn Gly His85 90 95Ser Glu Ser Ser Gly Gln Thr His Leu Glu Gly Asp Thr Val Gln Ile
100 105 110Ile Cys Asn Thr Gly Tyr Arg Leu Gln Asn Asn Glu Asn Asn Ile Ser115 120 125Cys Val Glu Arg Gly Trp Ser Thr Pro Pro Lys Cys Arg Ser Thr Ile130 135 140Ser Ala Glu Lys Cys Gly Pro Pro Pro Pro Ile Asp Asn Gly Asp Ile145 150 155 160Thr Ser Phe Leu Leu Ser Val Tyr Ala Pro Gly Ser Ser Val Glu Tyr165 170 175Gln Cys Gln Asn Leu Tyr Gln Leu Glu Gly Asn Asn Gln Ile Thr Cys180 185 190Arg Asn Gly Gln Trp Ser Glu Pro Pro Lys Cys Leu Asp Pro Cys Val195 200 205Ile Ser Gln Glu Ile Met Glu Lys Tyr Asn Ile Lys Leu Lys Trp Thr210 215 220Asn Gln Gln Lys Leu Tyr Ser Arg Thr Gly Asp Ile Val Glu Phe Val225 230 235 240Cys Lys Ser Gly Tyr His Pro Thr Lys Ser His Ser Phe Arg Ala Met245 250 255Cys Gln Asn Gly Lys Leu Val Tyr Pro Ser Cys Glu Glu Lys260 265 270<210>36<211>313<212>PRT<213>人類(lèi)<400>36Met Glu Leu Asp Arg Ala Val Gly Val Leu Gly Ala Ala Thr Leu Leu1 5 10 15Leu Ser Phe Leu Gly Met Ala Trp Ala Leu Gln Ala Ala Asp Thr Cys20 25 30Pro Glu Val Lys Met Val Gly Leu Glu Gly Ser Asp Lys Leu Thr Ile35 40 45Leu Arg Gly Cys Pro Gly Leu Pro Gly Ala Pro Gly Asp Lys Gly Glu50 55 60Ala Gly Thr Asn Gly Lys Arg Gly Glu Arg Gly Pro Pro Gly Pro Pro65 70 75 80Gly Lys Ala Gly Pro Pro Gly Pro Asn Gly Ala Pro Gly Glu Pro Gln85 90 95Pro Cys Leu Thr Gly Pro Arg Thr Cys Lys Asp Leu Leu Asp Arg Gly100 105 110His Phe Leu Ser Gly Trp His Thr Ile Tyr Leu Pro Asp Cys Arg Pro
115 120 125Leu Thr Val Leu Cys Asp Met Asp Thr Asp Gly Gly Gly Trp Thr Val130 135 140Phe Gln Arg Arg Val Asp Gly Ser Val Asp Phe Tyr Arg Asp Trp Ala145 150 155 160Thr Tyr Lys Gln Gly Phe Gly Ser Arg Leu Gly Glu Phe Trp Leu Gly165 170 175Asn Asp Asn Ile His Ala Leu Thr Ala Gln Gly Thr Ser Glu Leu Arg180 185 190Val Asp Leu Val Asp Phe Glu Asp Asn Tyr Gln Phe Ala Lys Tyr Arg195 200 205Ser Phe Lys Val Ala Asp Glu Ala Glu Lys Tyr Asn Leu Val Leu Gly210 215 220Ala Phe Val Glu Gly Ser Ala Gly Asp Ser Leu Thr Phe His Asn Asn225 230 235 240Gln Ser Phe Ser Thr Lys Asp Gln Asp Asn Asp Leu Asn Thr Gly Asn245 250 255Cys Ala Val Met Phe Gln Gly Ala Trp Trp Tyr Lys Asn Cys His Val260 265 270Ser Asn Leu Asn Gly Arg Tyr Leu Arg Gly Thr His Gly Ser Phe Ala275 280 285Asn Gly Ile Asn Trp Lys Ser Gly Lys Gly Tyr Asn Tyr Ser Tyr Lys290 295 300Val Ser Glu Met Lys Val Arg Pro Ala305 310<210>37<211>299<212>PRT<213>人類(lèi)<400>37Met Asp Leu Leu Trp Ile Leu Pro Ser Leu Trp Leu Leu Leu Leu Gly1 5 10 15Gly Pro Ala Cys Leu Lys Thr Gln Glu His Pro Ser Cys Pro Gly Pro20 25 30Arg Glu Leu Glu Ala Ser Lys Val Val Leu Leu Pro Ser Cys Pro Gly35 40 45Ala Pro Gly Ser Pro Gly Glu Lys Gly Ala Pro Gly Pro Gln Gly Pro50 55 60Pro Gly Pro Pro Gly Lys Met Gly Pro Lys Gly Glu Pro Gly Asp Pro65 70 75 80Val Asn Leu Leu Arg Cys Gln Glu Gly Pro Arg Asn Cys Arg Glu Leu
85 90 95Leu Ser Gln Gly Ala Thr Leu Ser Gly Trp Tyr His Leu Cys Leu Pro100 105 110Glu Gly Arg Ala Leu Pro Val Phe Cys Asp Met Asp Thr Glu Gly Gly115 120 125Gly Trp Leu Val Phe Gln Arg Arg Gln Asp Gly Ser Val Asp Phe Phe130 135 140Arg Ser Trp Ser Ser Tyr Arg Ala Gly Phe Gly Asn Gln Glu Ser Glu145 150 155 160Phe Trp Leu Gly Asn Glu Asn Leu His Gln Leu Thr Leu Gln Gly Asn165 170 175Trp Glu Leu Arg Val Glu Leu Glu Asp Phe Asn Gly Asn Arg Thr Phe180 185 190Ala His Tyr Ala Thr Phe Arg Leu Leu Gly Glu Val Asp His Tyr Gln195 200 205Leu Ala Leu Gly Lys Phe Ser Glu Gly Thr Ala Gly Asp Ser Leu Ser210 215 220Leu His Ser Gly Arg Pro Phe Thr Thr Tyr Asp Ala Asp His Asp Ser225 230 235 240Ser Asn Ser Asn Cys Ala Val Ile Val His Gly Ala Trp Trp Tyr Ala245 250 255Ser Cys Tyr Arg Ser Asn Leu Asn Gly Arg Tyr Ala Val Ser Asp Ala260 265 270Ala Ala His Lys Tyr Gly Ile Asp Trp Ala Ser Gly Arg Gly Val Gly275 280 285His Pro Tyr Arg Arg Val Arg Met Met Leu Arg290 295<210>38<211>782<212>PRT<213>人類(lèi)<400>38Met Ala Pro His Arg Pro Ala Pro Ala Leu Leu Cys Ala Leu Ser Leu1 5 10 15Ala Leu Cys Ala Leu Ser Leu Pro Val Arg Ala Ala Thr Ala Ser Arg20 25 30Gly Ala Ser Gln Ala Gly Ala Pro Gln Gly Arg Val Pro Glu Ala Arg35 40 45Pro Asn Ser Met Val Val Glu His Pro Glu Phe Leu Lys Ala Gly Lys50 55 60Glu Pro Gly Leu Gln Ile Trp Arg Val Glu Lys Phe Asp Leu Val Pro
65 70 75 80Val Pro Thr Asn Leu Tyr Gly Asp Phe Phe Thr Gly Asp Ala Tyr Val85 90 95Ile Leu Lys Thr Val Gln Leu Arg Asn Gly Asn Leu Gln Tyr Asp Leu100 105 110His Tyr Trp Leu Gly Asn Glu Cys Ser Gln Asp Glu Ser Gly Ala Ala115 120 125Ala Ile Phe Thr Val Gln Leu Asp Asp Tyr Leu Asn Gly Arg Ala Val130 135 140Gln His Arg Glu Val Gln Gly Phe Glu Ser Ala Thr Phe Leu Gly Tyr145 150 155 160Phe Lys Ser Gly Leu Lys Tyr Lys Lys Gly Gly Val Ala Ser Gly Phe165 170 175Lys His Val Val Pro Asn Glu Val Val Val Gln Arg Leu Phe Gln Val180 185 190Lys Gly Arg Arg Val Val Arg Ala Thr Glu Val Pro Val Ser Trp Glu195 200 205Ser Phe Asn Asn Gly Asp Cys Phe Ile Leu Asp Leu Gly Asn Asn Ile210 215 220His Gln Trp Cys Gly Ser Asn Ser Asn Arg Tyr Glu Arg Leu Lys Ala225 230 235 240Thr Gln Val Ser Lys Gly Ile Arg Asp Asn Glu Arg Ser Gly Arg Ala245 250 255Arg Val His Val Ser Glu Glu Gly Thr Glu Pro Glu Ala Met Leu Gln260 265 270Val Leu Gly Pro Lys Pro Ala Leu Pro Ala Gly Thr Glu Asp Thr Ala275 280 285Lys Glu Asp Ala Ala Asn Arg Lys Leu Ala Lys Leu Tyr Lys Val Ser290 295 300Asn Gly Ala Gly Thr Met Ser Val Ser Leu Val Ala Asp Glu Asn Pro305 310 315 320Phe Ala Gln Gly Ala Leu Lys Ser Glu Asp Cys Phe Ile Leu Asp His325 330 335Gly Lys Asp Gly Lys Ile Phe Val Trp Lys Gly Lys Gln Ala Asn Thr340 345 350Glu Glu Arg Lys Ala Ala Leu Lys Thr Ala Ser Asp Phe Ile Thr Lys355 360 365Met Asp Tyr Pro Lys Gln Thr Gln Val Ser Val Leu Pro Glu Gly Gly370 375 380Glu Thr Pro Leu Phe Lys Gln Phe Phe Lys Asn Trp Arg Asp Pro Asp385 390 395 400Gln Thr Asp Gly Leu Gly Leu Ser Tyr Leu Ser Ser His Ile Ala Asn405 410 415Val Glu Arg Val Pro Phe Asp Ala Ala Thr Leu His Thr Ser Thr Ala
420 425 430Met Ala Ala Gln His Gly Met Asp Asp Asp Gly Thr Gly Gln Lys Gln435 440 445Ile Trp Arg Ile Glu Gly Ser Asn Lys Val Pro Val Asp Pro Ala Thr450 455 460Tyr Gly Gln Phe Tyr Gly Gly Asp Ser Tyr Ile Ile Leu Tyr Asn Tyr465 470 475 480Arg His Gly Gly Arg Gln Gly Gln Ile Ile Tyr Asn Trp Gln Gly Ala485 490 495Gln Ser Thr Gln Asp Glu Val Ala Ala Ser Ala Ile Leu Thr Ala Gln500 505 510Leu Asp Glu Glu Leu Gly Gly Thr Pro Val Gln Ser Arg Val Val Gln515 520 525Gly Lys Glu Pro Ala His Leu Met Ser Leu Phe Gly Gly Lys Pro Met530 535 540Ile Ile Tyr Lys Gly Gly Thr Ser Arg Glu Gly Gly Gln Thr Ala Pro545 550 555 560Ala Ser Thr Arg Leu Phe Gln Val Arg Ala Asn Ser Ala Gly Ala Thr565 570 575Arg Ala Val Glu Val Leu Pro Lys Ala Gly Ala Leu Asn Ser Asn Asp580 585 590Ala Phe Val Leu Lys Thr Pro Ser Ala Ala Tyr Leu Trp Val Gly Thr595 600 605Gly Ala Ser Glu Ala Glu Lys Thr Gly Ala Gln Glu Leu Leu Arg Val610 615 620Leu Arg Ala Gln Pro Val Gln Val Ala Glu Gly Ser Glu Pro Asp Gly625 630 635 640Phe Trp Gla Ala Leu Gly Gly Lys Ala Ala Tyr Arg Thr Ser Pro Arg645 650 655Leu Lys Asp Lys Lys Met Asp Ala His Pro Pro Arg Leu Phe Ala Cys660 665 670Ser Asn Lys Ile Gly Arg Phe Val Ile Glu Glu Val Pro Gly Glu Leu675 680 685Met Gln Glu Asp Leu Ala Thr Asp Asp Val Met Leu Leu Asp Thr Trp690 695 700Asp Gln Val Phe Val Trp Val Gly Lys Asp Ser Gln Glu Glu Glu Lys705 710 715 720Thr Glu Ala Leu Thr Ser Ala Lys Arg Tyr Ile Glu Thr Asp Pro Ala725 730 735Asn Arg Asp Arg Arg Thr Pro Ile Thr Val Val Lys Gln Gly Phe Glu740 745 750Pro Pro Ser Phe Val Gly Trp Phe Leu Gly Trp Asp Asp Asp Tyr Trp755 760 765Ser Val Asp Pro Leu Asp Arg Ala Met Ala Glu Leu Ala Ala
770 775 780<210>39<211>406<212>PRT<213>人類(lèi)<400>39Met Ser Ala Leu Gly Ala Val Ile Ala Leu Leu Leu Trp Gly Gln Leu1 5 10 15Phe Ala Val Asp Ser Gly Asn Asp Val Thr Asp Ile Ala Asp Asp Gly20 25 30Cys Pro Lys Pro Pro Glu Ile Ala His Gly Tyr Val Glu His Ser Val35 40 45Arg Tyr Gln Cys Lys Asn Tyr Tyr Lys Leu Arg Thr Glu Gly Asp Gly50 55 60Val Tyr Thr Leu Asn Asp Lys Lys Gln Trp Ile Asn Lys Ala Val Gly65 70 75 80Asp Lys Leu Pro Glu Cys Glu Ala Asp Asp Gly Cys Pro Lys Pro Pro85 90 95Glu Ile Ala His Gly Tyr Val Glu His Ser Val Arg Tyr Gln Cys Lys100 105 110Asn Tyr Tyr Lys Leu Arg Thr Glu Gly Asp Gly Val Tyr Thr Leu Asn115 120 125Asn Glu Lys Gln Trp Ile Asn Lys Ala Val Gly Asp Lys Leu Pro Glu130 135 140Cys Glu Ala Val Cys Gly Lys Pro Lys Asn Pro Ala Asn Pro Val Gln145 150 155 160Arg Ile Leu Gly Gly His Leu Asp Ala Lys Gly Ser Phe Pro Trp Gln165 170 175Ala Lys Met Val Ser His His Asn Leu Thr Thr Gly Ala Thr Leu Ile180 185 190Asn Glu Gln Trp Leu Leu Thr Thr Ala Lys Asn Leu Phe Leu Asn His195 200 205Ser Glu Asn Ala Thr Ala Lys Asp Ile Ala Pro Thr Leu Thr Leu Tyr210 215 220Val Gly Lys Lys Gln Leu Val Glu Ile Glu Lys Val Val Leu His Pro225 230 235 240Asn Tyr Ser Gln Val Asp Ile Gly Leu Ile Lys Leu Lys Gln Lys Val245 250 255Ser Val Asn Glu Arg Val Met Pro Ile Cys Leu Pro Ser Lys Asp Tyr260 265 270Ala Glu Val Gly Arg Val Gly Tyr Val Ser Gly Trp Gly Arg Asn Ala
275 280 285Asn Phe Lys Phe Thr Asp His Leu Lys Tyr Val Met Leu Pro Val Ala290 295 300Asp Gln Asp Gln Cys Ile Arg His Tyr Glu Gly Ser Thr Val Pro Glu305 310 315 320Lys Lys Thr Pro Lys Ser Pro Val Gly Val Gln Pro Ile Leu Asn Glu325 330 335His Thr Phe Cys Ala Gly Met Ser Lys Tyr Gln Glu Asp Thr Cys Tyr340 345 350Gly Asp Ala Gly Ser Ala Phe Ala Val His Asp Leu Glu Glu Asp Thr355 360 365Trp Tyr Ala Thr Gly Ile Leu Ser Phe Asp Lys Ser Cys Ala Val Ala370 375 380Glu Tyr Gly Val Tyr Val Lys ValThr Ser Ile Gln Asp Trp Val Gln385 390 395 400Lys Thr Ile Ala Glu Asn405<210>40<211>348<212>PRT<213>人類(lèi)<400>40Met Ser Asp Leu Gly Ala Val Ile Ser Leu Leu Leu Trp Gly Arg Gln1 5 10 15Leu Phe Ala Leu Tyr Ser Gly Asn Asp Val Thr Asp Ile Ser Asp Asp20 25 30Arg Phe Pro Lys Pro Pro Glu Ile Ala Asn Gly Tyr Val Glu His Leu35 40 45Phe Arg Tyr Gln Cys Lys Asn Tyr Tyr Arg Leu Arg Thr Glu Gly Asp50 55 60Gly Val Tyr Thr Leu Asn Asp Lys Lys Gln Trp Ile Asn Lys Ala Val65 70 75 80Gly Asp Lys Leu Pro Glu Cys Glu Ala Val Cys Gly Lys Pro Lys Asn85 90 95Pro Ala Asn Pro Val Gln Arg Ile Leu Gly Gly His Leu Asp Ala Lys100 105 110Gly Ser Phe Pro Trp Gln Ala Lys Met Val Ser His His Asn Leu Thr115 120 125Thr Gly Ala Thr Leu Ile Asn G1u Gln Trp Leu Leu Thr Thr Ala Lys130 135 140Asn Leu Phe Leu Asn His Ser Glu Asn Ala Thr Ala Lys Asp Ile Ala
145 150 155160Pro Thr Leu Thr Leu Tyr Val Gly Lys Lys Gln Leu Val Glu Ile Glu165 170 175Lys Val Val Leu His Pro Asn Tyr His Gln Val Asp Ile Gly Leu Ile180 185 190Lys Leu Lys Gln Lys Val Leu Val Asn Glu Arg Val Met Pro Ile Cys195 200205Leu Pro Ser Lys Asn Tyr Ala Glu Val Gly Arg Val Gly Tyr Val Ser210 215 220Gly Trp Gly Gln Ser Asp Asn Phe Lys Leu Thr Asp His Leu Lys Tyr225 230 235 240Val Met Leu Pro Val Ala Asp Gln Tyr Asp Cys Ile Thr His Tyr Glu245 250 255Gly Ser Thr Cys Pro Lys Trp Lys Ala Pro Lys Ser Pro Val Gly Val260 265 270Gln Pro Ile Leu Asn Glu His Thr Phe Cys Val Gly Met Ser Lys Tyr275 280 285Gln Glu Asp Thr Cys Tyr Gly Asp Ala Gly Ser Ala Phe Ala Val His290 295 300Asp Leu Glu Glu Asp Thr Trp Tyr Ala Ala Gly Ile Leu Ser Phe Asp305 310 315 320Lys Ser Cys Ala Val Ala Glu Tyr Gly Val Tyr Val Lys Val Thr Ser325 330 335Ile Gln Asp Trp Val Gln Lys Thr Ile Ala Glu Asn340 345<210>41<211>462<212>PRT<213>人類(lèi)<400>41Met Ala Arg Val Leu Gly Ala Pro Val Ala Leu Gly Leu Trp Ser Leu1 5 10 15Cys Trp Ser Leu Ala Ile Ala Thr Pro Leu Pro Pro Thr Ser Ala His20 25 30Gly Asn Val Ala Glu Gly Glu Thr Lys Pro Asp Pro Asp Val Thr Glu35 40 45Arg Cys Ser Asp Gly Trp Ser Phe Asp Ala Thr Thr Leu Asp Asp Asn50 55 60Gly Thr Met Leu Phe Phe Lys Gly Glu Phe Val Trp Lys Ser His Lys65 70 75 80Trp Asp Arg Glu Leu Ile Ser Glu Arg Trp Lys Asn Phe Pro Ser Pro
85 90 95Val Asp Ala Ala Phe Arg Gln Gly His Asn Ser Val Phe Leu Ile Lys100 105 110Gly Asp Lys Val Trp Val Tyr Pro Pro Glu Lys Lys Glu Lys Gly Tyr115 120 125Pro Lys Leu Leu Gln Asp Glu Phe Pro Gly Ile Pro Ser Pro Leu Asp130 135 140Ala Ala Val Glu Cys His Arg Gly Glu Cys Gln Ala Glu Gly Val Leu145 150 155 160Phe Phe Gln Gly Asp Arg Glu Trp Phe Trp Asp Leu Ala Thr Gly Thr165 170 175Met Lys Glu Arg Ser Trp Pro Ala Val Gly Asn Cys Ser Ser Ala Leu180 185 190Arg Trp Leu Gly Arg Tyr Tyr Cys Phe Gln Gly Asn Gln Phe Leu Arg195 200 205Phe Asp Pro Val Arg Gly Glu Val Pro Pro Arg Tyr Pro Arg Asp Val210 215 220Arg Asp Tyr Phe Met Pro Cys Pro Gly Arg Gly His Gly His Arg Asn225 230 235 240Gly Thr Gly His Gly Asn Ser Thr His His Gly Pro Glu Tyr Met Arg245 250 255Cys Ser Pro His Leu Val Leu Ser Ala Leu Thr Ser Asp Asn His Gly260 265 270Ala Thr Tyr Ala Phe Ser Gly Thr His Tyr Trp Arg Leu Asp Thr Ser275 280 285Arg Asp Gly Trp His Ser Trp Pro Ile Ala His Gln Trp Pro Gln Gly290 295 300Pro Ser Ala Val Asp Ala Ala Phe Ser Trp Glu Glu Lys Leu Tyr Leu305 310 315 320Val Gln Gly Thr Gln Val Tyr Val Phe Leu Thr Lys Gly Gly Tyr Thr325 330 335Leu Val Ser Gly Tyr Pro Lys Arg Leu Glu Lys Glu Val Gly Thr Pro340 345 350His Gly Ile Ile Leu Asp Ser Val Asp Ala Ala Phe Ile Cys Pro Gly355 360 365Ser Ser Arg Leu His Ile Met Ala Gly Arg Arg Leu Trp Trp Leu Asp370 375 380Leu Lys Ser Gly Ala Gln Ala Thr Trp Thr Glu Leu Pro Trp Pro His385 390 395 400Glu Lys Val Asp Gly Ala Leu Cys Met Glu Lys Ser Leu Gly Pro Asn405 410 415Ser Cys Ser Ala Asn Gly Pro Gly Leu Tyr Leu Ile His Gly Pro Asn420 425 430Leu Tyr Cys Tyr Ser Asp Val Glu Lys Leu Asn Ala Ala Lys Ala Leu
435 440 445Pro Gln Pro Gln Asn Val Thr Ser Leu Leu Gly Cys Thr His450 455 460<210>42<211>930<212>PRT<213>人類(lèi)<400>42Met Lys Pro Pro Arg Pro Val Arg Thr Cys Ser Lys Val Leu Val Leu1 5 10 15Leu Ser Leu Leu Ala Ile His Gln Thr Thr Thr Ala Glu Lys Asn Gly20 25 30Ile Asp Ile Tyr Ser Leu Thr Val Asp Ser Arg Val Ser Ser Arg Phe35 40 45Ala His Thr Val Val Thr Ser Arg Val Val Asn Arg Ala Asn Thr Val50 55 60Gln Glu Ala Thr Phe Gln Met Glu Leu Pro Lys Lys Ala Phe Ile Thr65 70 75 80Asn Phe Ser Met Asn Ile Asp Gly Met Thr Tyr Pro Gly Ile Ile Lys85 90 95Glu Lys Ala Glu Ala Gln Ala Gln Tyr Ser Ala Ala Val Ala Lys Gly100 105 110Lys Ser Ala Gly Leu Val Lys Ala Thr Gly Arg Asn Met Glu Gln Phe115 120 125Gln Val Ser Val Ser Val Ala Pro Asn Ala Lys Ile Thr Phe Glu Leu130 135 140Val Tyr Glu Glu Leu Leu Lys Arg Arg Leu Gly Val Tyr Glu Leu Leu145 150 155 160Leu Lys Val Arg Pro Gln Gln Leu Val Lys His Leu Gln Met Asp Ile165 170 175His Ile Phe Glu Pro Gln Gly Ile Ser Phe Leu Glu Thr Glu Ser Thr180 185 190Phe Met Thr Asn Gln Leu Val Asp Ala Leu Thr Thr Trp Gln Asn Lys195 200 205Thr Lys Ala His Ile Arg Phe Lys Pro Thr Leu Ser Gln Gln Gln Lys210 215 220Ser Pro Glu Gln Gln Glu Thr Val Leu Asp Gly Asn Leu Ile Ile Arg225 230 235 240Tyr Asp Val Asp Arg Ala Ile Ser Gly Gly Ser Ile Gln Ile Glu Asn245 250 255Gly Tyr Phe Val His Tyr Phe Ala Pro Glu Gly Leu Thr Thr Met Pro
260 265 270Lys Asn Val Val Phe Val Ile Asp Lys Ser Gly Ser Met Ser Gly Arg275 280 285Lys Ile Gln Gln Thr Arg Glu Ala Leu Ile Lys Ile Leu Asp Asp Leu290 295 300Ser Pro Arg Asp Gln Phe Asn Leu Ile Val Phe Ser Thr Glu Ala Thr305 310 315 320Gln Trp Arg Pro Ser Leu Val Pro Ala Ser Ala Glu Asn Val Asn Lys325 330 335Ala Arg Ser Phe Ala Ala Gly Ile Gln Ala Leu Gly Gly Thr Asn Ile340 345 350Asn Asp Ala Met Leu Met Ala Val Gln Leu Leu Asp Ser Ser Asn Gln355 360 365Glu Glu Arg Leu Pro Glu Gly Ser Val Ser Leu Ile Ile Leu Leu Thr370 375 380Asp Gly Asp Pro Thr Val Gly Glu Thr Asn Pro Arg Ser Ile Gln Asn385 390 395 400Asn Val Arg Glu Ala Val Ser Gly Arg Tyr Ser Leu Phe Cys Leu Gly405 410 415Phe Gly Phe Asp Val Ser Tyr Ala Phe Leu Glu Lys Leu Ala Leu Asp420 425 430Asn Gly Gly Leu Ala Arg Arg Ile His Glu Asp Ser Asp Ser Ala Leu435 440 445Gln Leu Gln Asp Phe Tyr Gln Glu Val Ala Asn Pro Leu Leu Thr Ala450 455 460Val Thr Phe Glu Tyr Pro Ser Asn Ala Val Glu Glu Val Thr Gln Asn465 470 475 480Asn Phe Arg Leu Leu Phe Lys Gly Ser Glu Met Val Val Ala Gly Lys485 490 495Leu Gln Asp Arg Gly Pro Asp Val Leu Thr Ala Thr Val Ser Gly Lys500 505 510Leu Pro Thr Gln Asn Ile Thr Phe Gln Thr Glu Ser Ser Val Ala Glu515 520 525Gln Glu Ala Glu Phe Gln Ser Pro Lys Tyr Ile Phe His Asn Phe Met530 535 540Glu Arg Leu Trp Ala Tyr Leu Thr Ile Gln Gln Leu Leu Glu Gln Thr545 550 555 560Val Ser Ala Ser Asp Ala Asp Gln Gln Ala Leu Arg Asn Gln Ala Leu565 570 575Asn Leu Ser Leu Ala Tyr Ser Phe Val Thr Pro Leu Thr Ser Met Val580 585 590Val Thr Lys Pro Asp Asp Gln Glu Gln Ser Gln Val Ala Glu Lys Pro595 600 605Met Glu Gly Glu Ser Arg Asn Arg Asn Val His Ser Gly Ser Thr Phe
610 615 620Phe Lys Tyr Tyr Leu Gln Gly Ala Lys Ile Pro Lys Pro Glu Ala Ser625 630 635 640Phe Ser Pro Arg Arg Gly Trp Asn Arg Gln Ala Gly Ala Ala Gly Ser645 650 655Arg Met Asn Phe Arg Pro Gly Val Leu Ser Ser Arg Gln Leu Gly Leu660 665 670Pro Gly Pro Pro Asp Val Pro Asp His Ala Ala Tyr His Pro Phe Arg675 680 685Arg Leu Ala Ile Leu Pro Ala Ser Ala Pro Pro Ala Thr Ser Asn Pro690 695 700Asp Pro Ala Val Ser Arg Val Met Asn Met Lys Ile Glu Glu Thr Thr705 710 715 720Met Thr Thr Gln Thr Pro Ala Pro Ile Gln Ala Pro Ser Ala Ile Leu725 730 735Pro Leu Pro Gly Gln Ser Val Glu Arg Leu Cys Val Asp Pro Arg His740 745 750Arg Gln Gly Pro Val Asn Leu Leu Ser Asp Pro Glu Gln Gly Val Glu755 760 765Val Thr Gly Gln Tyr Glu Arg Glu Lys Ala Gly Phe Ser Trp Ile Glu770 775 780Val Thr Phe Lys Asn Pro Leu Val Trp Val His Ala Ser Pro Glu His785 790 795 800Val Val Val Thr Arg Asn Arg Arg Ser Ser Ala Tyr Lys Trp Lys Glu805 810 815Thr Leu Phe Ser Val Met Pro Gly Leu Lys Met Thr Met Asp Lys Thr820 825 830Gly Leu Leu Leu Leu Ser Asp Pro Asp Lys Val Thr Ile Gly Leu Leu835 840 845Phe Trp Asp Gly Arg Gly Glu Gly Leu Arg Leu Leu Leu Arg Asp Thr850 855 860Asp Arg Phe Ser Ser His Val Gly Gly Thr Leu Gly Gln Phe Tyr Gln865 870 875 880Glu Val Leu Trp Gly Ser Pro Ala Ala Ser Asp Asp Gly Arg Arg Thr885 890 895Leu Arg Val Gln Gly Ash Asp His Ser Ala Thr Arg Glu Arg Arg Leu900 905 910Asp Tyr Gln Glu Gly Pro Pro Gly Val Glu Ile Ser Cys Trp Ser Val915 920 925Glu Leu930<210>43
<211>165<212>PRT<213>人類(lèi)<400>43Met Val Asn Pro Thr Val Phe Phe Asp Ile Ala Val Asp Gly Glu Pro1 5 10 15Leu Gly Arg Val Ser Phe Glu Leu Phe Ala Asp Lys Val Pro Lys Thr20 25 30Ala Glu Asn Phe Arg Ala Leu Ser Thr Gly Glu Lys Gly Phe Gly Tyr35 40 45Lys Gly Ser Cys Phe His Arg Ile Ile Pro Gly Phe Met Cys Gln Gly50 55 60Gly Asp Phe Thr Arg His Asn Gly Thr Gly Gly Lys Ser Ile Tyr Gly65 70 75 80Glu Lys Phe Glu Asp Glu Asn Phe Ile Leu Lys His Thr Gly Pro Gly85 90 95Ile Leu Ser Met Ala Asn Ala Gly Pro Asn Thr Asn Gly Ser Gln Phe100 105 110Phe Ile Cys Thr Ala Lys Thr Glu Trp Leu Asp Gly Lys His Val Val115 120 125Phe Gly Lys Val Lys Glu Gly Met Asn Ile Val Glu Ala Met Glu Arg130 135 140Phe Gly Ser Arg Asn Gly Lys Thr Ser Lys Lys Ile Thr Ile Ala Asp145 150 155 160Cys Gly Gln Leu Glu165<210>44<211>226<212>PRT<213>人類(lèi)<400>44Met Ala Arg Leu Leu Gln Ala Ser Cys Leu Leu Ser Leu Leu Leu Ala1 5 10 15Gly Phe Val Ser Gln Ser Arg Gly Gln Glu Lys Ser Lys Met Asp Cys20 25 30His Gly Gly Ile Ser Gly Thr Ile Tyr Glu Tyr Gly Ala Leu Thr Ile35 40 45Asp Gly Glu Glu Tyr Ile Pro Phe Lys Gln Tyr Ala Gly Lys Tyr Val50 55 60Leu Phe Val Asn Val Ala Ser Tyr Cys Gly Leu Thr Gly Gln Tyr Ile
65 70 75 80Glu Leu Asn Ala Leu Gln Glu Glu Leu Ala Pro Phe Gly Leu Val Ile85 90 95Leu Gly Phe Pro Cys Asn Gln Phe Gly Lys Gln Glu Pro Gly Glu Asn100 105 110Ser Glu Ile Leu Pro Thr Leu Lys Tyr Val Arg Pro Gly Gly Gly Phe115 120 125Val Pro Asn Phe Gln Leu Phe Glu Lys Gly Asp Val Asn Gly Glu Lys130 135 140Glu Gln Lys Phe Tyr Thr Phe Leu Lys Asn Ser Cys Pro Pro Thr Ser145 150 155 160Glu Leu Leu Gly Thr Ser Asp Arg Leu Phe Trp Glu Pro Met Lys Val165 170 175His Asp Ile Arg Trp Asn Phe Glu Lys Phe Leu Val Gly Pro Asp Gly180 185 190Ile Pro Ile Met Arg Trp His His Arg Thr Thr Val Ser Asn Val Lys195 200 205Met Asp Ile Leu Ser Tyr Met Arg Arg Gln Ala Ala Leu Gly Val Lys210 215 220Arg Lys225<210>45<211>128<212>PRT<213>人類(lèi)<400>45Met Ser Leu Arg Leu Asp Thr Thr Pro Ser Cys Asn Ser Ala Arg Pro1 5 10 15Leu His Ala Leu Gln Val Leu Leu Leu Leu Ser Leu Leu Leu Thr Ala20 25 30Leu Ala Ser Ser Thr Lys Gly Gln Thr Lys Arg Asn Leu Ala Lys Gly35 40 45Lys Glu Glu Ser Leu Asp Ser Asp Leu Tyr Ala Glu Leu Arg Cys Met50 55 60Cys Ile Lys Thr Thr Ser Gly Ile His Pro Lys Asn Ile Gln Ser Leu65 70 75 80Glu Val Ile Gly Lys Gly Thr His Cys Asn Gln Val Glu Val Ile Ala85 90 95Thr Leu Lys Asp Gly Arg Lys Ile Cys Leu Asp Pro Asp Ala Pro Arg100 105 110Ile Lys Lys Ile Val Gln Lys Lys Leu Ala Gly Asp Glu Ser Ala Asp
115 120 125<210>46<211>698<212>PRT<213>人類(lèi)<400>46Met Arg Leu Ala Val Gly Ala Leu Leu Val Cys Ala Val Leu Gly Leu1 5 10 15Cys Leu Ala Val Pro Asp Lys Thr Val Arg Trp Cys Ala Val Ser Glu20 25 30His Glu Ala Thr Lys Cys Gln Ser Phe Arg Asp His Met Lys Ser Val35 40 45Ile Pro Ser Asp Gly Pro Ser Val Ala Cys Val Lys Lys Ala Ser Tyr50 55 60Leu Asp Cys Ile Arg Ala Ile Ala Ala Asn Glu Ala Asp Ala Val Thr65 70 75 80Leu Asp Ala Gly Leu Val Tyr Asp Ala Tyr Leu Ala Pro Asn Asn Leu85 90 95Lys Pro Val Val Ala Glu Phe Tyr Gly Ser Lys Glu Asp Pro Gln Thr100 105 110Phe Tyr Tyr Ala Val Ala Val Val Lys Lys Asp Ser Gly Phe Gln Met115 120 125Asn Gln Leu Arg Gly Lys Lys Ser Cys His Thr Gly Leu Gly Arg Ser130 135 140Ala Gly Trp Asn Ile Pro Ile Gly Leu Leu Tyr Cys Asp Leu Pro Glu145 150 155 160Pro Arg Lys Pro Leu Glu Lys Ala Val Ala Asn Phe Phe Ser Gly Ser165 170 175Cys Ala Pro Cys Ala Asp Gly Thr Asp Phe Pro Gln Leu Cys Gln Leu180 185 190Cys Pro Gly Cys Gly Cys Ser Thr Leu Asn Gln Tyr Phe Gly Tyr Ser195 200 205Gly Ala Phe Lys Cys Leu Lys Asp Gly Ala Gly Asp Val Ala Phe Val210 215 220Lys His Ser Thr Ile Phe Glu Asn Leu Ala Asn Lys Ala Asp Arg Asp225 230 235 240Gln Tyr Glu Leu Leu Cys Leu Asp Asn Thr Arg Lys Pro Val Asp Glu245 250 255Tyr Lys Asp Cys His Leu Ala Gln Val Pro Ser His Thr Val Val Ala260 265 270Arg Ser Met Gly Gly Lys Glu Asp Leu Ile Trp Glu Leu Leu Asn Gln
275 280 285Ala Gln Glu His Phe Gly Lys Asp Lys Ser Lys Glu Phe Gln Leu Phe290 295 300Ser Ser Pro His Gly Lys Asp Leu Leu Phe Lys Asp Ser Ala His Gly305 310 315 320Phe Leu Lys Val Pro Pro Arg Met Asp Ala Lys Met Tyr Leu Gly Tyr325 330 335Glu Tyr Val Thr Ala Ile Arg Asn Leu Arg Glu Gly Thr Cys Pro Glu340 345 350Ala Pro Thr Asp Glu Cys Lys Pro Val Lys Trp Cys Ala Leu Ser His355 360 365His Glu Arg Leu Lys Cys Asp Glu Trp Ser Val Asn Ser Val Gly Lys370 375 380Ile Glu Cys Val Ser Ala Glu Thr Thr Glu Asp Cys Ile Ala Lys Ile385 390 395 400Met Asn Gly Glu Ala Asp Ala Met Ser Leu Asp Gly Gly Phe Val Tyr405 410 415Ile Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala Glu Asn Tyr Asn420 425 430Lys Ser Asp Asn Cys Glu Asp Thr Pro Glu Ala Gly Tyr Phe Ala Val435 440 445Ala Val Val Lys Lys Ser Ala Ser Asp Leu Thr Trp Asp Asn Leu Lys450 455 460Gly Lys Lys Ser Cys His Thr Ala Val Gly Arg Thr Ala Gly Trp Asn465 470 475 480Ile Pro Met Gly Leu Leu Tyr Asn Lys Ile Asn His Cys Arg Phe Asp485 490 495Glu Phe Phe Ser Glu Gly Cys Ala Pro Gly Ser Lys Lys Asp Ser Ser500 505 510Leu Cys Lys Leu Cys Met Gly Ser Gly Leu Asn Leu Cys Glu Pro Asn515 520 525Asn Lys Glu Gly Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Val530 535 540Glu Lys Gly Asp Val Ala Phe Val Lys His Gln Thr Val Pro Gln Asn545 550 555 560Thr Gly Gly Lys Asn Pro Asp Pro Trp Ala Lys Asn Leu Asn Glu Lys565 570 575Asp Tyr Glu Leu Leu Cys Leu Asp Gly Thr Arg Lys Pro Val Glu Glu580 585 590Tyr Ala Asn Cys His Leu Ala Arg Ala Pro Asn His Ala Val Val Thr595 600 605Arg Lys Asp Lys Glu Ala Cys Val His Lys Ile Leu Arg Gln Gln Gln610 615 620His Leu Phe Gly Ser Asn Val Thr Asp Cys Ser Gly Asn Phe Cys Leu
625 630 635 640Phe Arg Ser Glu Thr Lys Asp Leu Leu Phe Arg Asp Asp Thr Val Cys645 650 655Leu Ala Lys Leu His Asp Arg Asn Thr Tyr Glu Lys Tyr Leu Gly Glu660 665 670Glu Tyr Val Lys Ala Val Gly Asn Leu Arg Lys Cys Ser Thr Ser Ser675 680 685Leu Leu Glu Ala Cys Thr Phe Arg Arg Pro690 695<210>47<211>122<212>PRT<213>人類(lèi)<400>47Met Lys Leu Leu Thr Gly Leu Val Phe Cys Ser Leu Val Leu Gly Val1 5 10 15Ser Ser Arg Ser Phe Phe Ser Phe Leu Gly Glu Ala Phe Asp Gly Ala20 25 30Arg Asp Met Trp Arg Ala Tyr Ser Asp Met Arg Glu Ala Asn Tyr Ile35 40 45Gly Ser Asp Lys Tyr Phe His Ala Arg Gly Asn Tyr Asp Ala Ala Lys50 55 60Arg Gly Pro Gly Gly Val Trp Ala Ala Glu Ala Ile Ser Asp Ala Arg65 70 75 80Glu Asn Ile Gln Arg Phe Phe Gly His Gly Ala Glu Asp Ser Leu Ala85 90 95Asp Gln Ala Ala Asn Glu Trp Gly Arg Ser Gly Lys Asp Pro Asn His100 105 110Phe Arg Pro Ala Gly Leu Pro Glu Lys Tyr115 120<210>48<211>130<212>PRT<213>人類(lèi)<400>48Met Arg Leu Phe Thr Gly Ile Val Phe Cys Ser Leu Val Met Gly Val1 5 10 15Thr Ser Glu Ser Trp Arg Ser Phe Phe Lys Glu Ala Leu Gln Gly Val
20 25 30Gly Asp Met Gly Arg Ala Tyr Trp Asp Ile Met Ile Ser Asn His Gln35 40 45Asn Ser Asn Arg Tyr Leu Tyr Ala Arg Gly Asn Tyr Asp Ala Ala Gln50 55 60Arg Gly Pro Gly Gly Val Trp Ala Ala Lys Leu Ile Ser Arg Ser Arg65 70 75 80Val Tyr Leu Gln Gly Leu Ile Asp Tyr Tyr Leu Phe Gly Asn Ser Ser85 90 95Thr Val Leu Glu Asp Ser Lys Ser Asn Glu Lys Ala Glu Glu Trp Gly100 105 110Arg Ser Gly Lys Asp Pro Asp Arg Phe Arg Pro Asp Gly Leu Pro Lys115 120 125Lys Tyr130<210>49<211>202<212>PRT<213>人類(lèi)<400>49Met Glu Leu Trp Gly Ala Tyr Leu Leu Leu Cys Leu Phe Ser Leu Leu1 5 10 15Thr Gln Val Thr Thr Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val20 25 30Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys35 40 45Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln50 55 60Gln Ala Leu Gln Thr Val Cys Leu Lys Gly Thr Lys Val His Met Lys65 70 75 80Cys Phe Leu Ala Phe Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu85 90 95Asp Cys Ile Ser Arg Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser100 105 110Glu Asn Asp Ala Leu Tyr Glu Tyr Leu Arg Gln Ser Val Gly Asn Glu115 120 125Ala Glu Ile Trp Leu Gly Leu Asn Asp Met Ala Ala Glu Gly Thr Trp130 135 140Val Asp Met Thr Gly Ala Arg Ile Ala Tyr Lys Asn Trp Glu Thr Glu145 150 155 160Ile Thr Ala Gln Pro Asp Gly Gly Lys Thr Glu Asn Cys Ala Val Leu
165 170 175Ser Gly Ala Ala Asn Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln180 185 190Leu Pro Tyr Ile Cys Gln Phe Gly Ile Val195 200<210>50<211>147<212>PRT<213>人類(lèi)<400>50Met Ala Ser His Arg Leu Leu Leu Leu Cys Leu Ala Gly Leu Val Phe1 5 10 15Val Ser Glu Ala Gly Pro Thr Gly Thr Gly Glu Ser Lys Cys Pro Leu20 25 30Met Val Lys Val Leu Asp Ala Val Arg Gly Ser Pro Ala Ile Asn Val35 40 45Ala Val His Val Phe Arg Lys Ala Ala Asp Asp Thr Trp Glu Pro Phe50 55 60Ala Ser Gly Lys Thr Ser Glu Ser Gly Glu Leu His Gly Leu Thr Thr65 70 75 80Glu Glu Glu Phe Val Glu Gly Ile Tyr Lys Val Glu Ile Asp Thr Lys85 90 95Ser Tyr Trp Lys Ala Leu Gly Ile Ser Pro Phe His Glu His Ala Glu100 105 110Val Val Phe Thr Ala Asn Asp Ser Gly Pro Arg Arg Tyr Thr Ile Ala115 120 125Ala Leu Leu Ser Pro Tyr Ser Tyr Ser Thr Thr Ala Val Val Thr Asn130 135 140Pro Lys Glu145<210>51<211>478<212>PRT<213>人類(lèi)<400>51Met Ala Pro Leu Arg Pro Leu Leu Ile Leu Ala Leu Leu Ala Trp Val1 5 10 15Ala Leu Ala Asp Gln Glu Ser Cys Lys Gly Arg Cys Thr Glu Gly Phe
20 25 30Asn Val Asp Lys Lys Cys Gln Cys Asp Glu Leu Cys Ser Tyr Tyr Gln35 40 45Ser Cys Cys Thr Asp Tyr Thr Ala Glu Cys Lys Pro Gln Val Thr Arg50 55 60Gly Asp Val Phe Thr Met Pro Glu Asp Glu Tyr Thr Val Tyr Asp Asp65 70 75 80Gly Glu Glu Lys Asn Asn Ala Thr Val His Glu Gln Val Gly Gly Pro85 90 95Ser Leu Thr Ser Asp Leu Gln Ala Gln Ser Lys Gly Asn Pro Glu Gln100 105 110Thr Pro Val Leu Lys Pro Glu Glu Glu Ala Pro Ala Pro Glu Val Gly115 120 125Ala Ser Lys Pro Glu Gly Ile Asp Ser Arg Pro Glu Thr Leu His Pro130 135 140Gly Arg Pro Gln Pro Pro Ala Glu Glu Glu Leu Cys Ser Gly Lys Pro145 150 155 160Phe Asp Ala Phe Thr Asp Leu Lys Asn Gly Ser Leu Phe Ala Phe Arg165 170 175Gly Gln Tyr Cys Tyr Glu Leu Asp Glu Lys Ala Val Arg Pro Gly Tyr180 185 190Pro Lys Leu Ile Arg Asp Val Trp Gly Ile Glu Gly Pro Ile Asp Ala195 200 205Ala Phe Thr Arg Ile Asn Cys Gln Gly Lys Thr Tyr Leu Phe Lys Gly210 215 220Ser Gln Tyr Trp Arg Phe Glu Asp Gly Val Leu Asp Pro Asp Tyr Pro225 230 235 240Arg Asn Ile Ser Asp Gly Phe Asp Gly Ile Pro Asp Asn Val Asp Ala245 250 255Ala Leu Ala Leu Pro Ala His Ser Tyr Ser Gly Arg Glu Arg Val Tyr260 265 270Phe Phe Lys Gly Lys Gln Tyr Trp Glu Tyr Gln Phe Gln His Gln Pro275 280 285Ser Gln Glu Glu Cys Glu Gly Ser Ser Leu Ser Ala Val Phe Glu His290 295 300Phe Ala Met Met Gln Arg Asp Ser Trp Glu Asp Ile Phe Glu Leu Leu305 310 315 320Phe Trp Gly Arg Thr Ser Ala Gly Thr Arg Gln Pro Gln Phe Ile Ser325 330 335Arg Asp Trp His Gly Val Pro Gly Gln Val Asp Ala Ala Met Ala Gly340 345 350Arg Ile Tyr Ile Ser Gly Met Ala Pro Arg Pro Ser Leu Ala Lys Lys355 360 365Gln Arg Phe Arg His Arg Asn Arg Lys Gly Tyr Arg Ser Gln Arg Gly
370 375 380His Ser Arg Gly Arg Asn Gln Asn Ser Arg Arg Pro Ser Arg Ala Thr385 390 395 400Trp Leu Ser Leu Phe Ser Ser Glu Glu Ser Asn Leu Gly Ala Asn Asn405 410 415Tyr Asp Asp Tyr Arg Met Asp Trp Leu Val Pro Ala Thr Cys Glu Pro420 425 430Ile Gln Ser Val Phe Phe Phe Ser Gly Asp Lys Tyr Tyr Arg Val Asn435 440 445Leu Arg Thr Arg Arg Val Asp Thr Val Asp Pro Pro Tyr Pro Arg Ser450 455 460Ile Ala Gln Tyr Trp Leu Gly Cys Pro Ala Pro Gly His Leu465 470 475<210>52<211>295<212>PRT<213>人類(lèi)<400>52Met Val Pro Val Leu Leu Ser Leu Leu Leu Leu Leu Gly Pro Ala Val1 5 10 15Pro Gln Glu Asn Gln Asp Gly Arg Tyr Ser Leu Thr Tyr Ile Tyr Thr20 25 30Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln Ala Leu Gly35 40 45Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys Asp Arg Lys50 55 60Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met Glu Asp Trp65 70 75 80Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile Phe Met Glu85 90 95Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser Asn Gly Ser His100 105 110Val Leu Gln Gly Arg Phe Gly Cys Glu Ile Glu Asn Asn Arg Ser Ser115 120 125Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly Lys Asp Tyr Ile Glu Phe130 135 140Asn Lys Glu Ile Pro Ala Trp Val Pro Phe Asp Pro Ala Ala Gln Ile145 150 155 160Thr Lys Gln Lys Trp Glu Ala Glu Pro Val Tyr Val Gln Arg Ala Lys165 170 175Ala Tyr Leu Glu Glu Glu Cys Pro Ala Thr Leu Arg Lys Tyr Leu Lys
180 185 190Tyr Ser Lys Asn Ile Leu Asp Arg Gln Asp Pro Pro Ser Val Val Val195 200 205Thr Ser His Gln Ala Pro Gly Glu Lys Lys Lys Leu Lys Cys Leu Ala210 215 220Tyr Asp Phe Tyr Pro Gly Lys Ile Asp Val His Trp Thr Arg Ala Gly225 230 235 240Glu Val Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His Asn Gly Asn245 250 255Gly Thr Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro Gln Asp Thr260 265 270Ala Pro Tyr Ser Cys His Val Gln His Ser Ser Leu Ala Gln Pro Leu275 280 285Val Val Pro Trp Glu Ala Ser290 295-1-RTA01/2184724v1？1？RTA01/2184724v權(quán)利要求
1.用于診斷患者的卵巢癌的方法，所述的方法包括檢測(cè)身體樣品中至少一種生物標(biāo)志的超表達(dá)，其中檢測(cè)所述生物標(biāo)志的超表達(dá)可特異性鑒定預(yù)示卵巢癌的樣品，且其中所述的生物標(biāo)志選自急性期反應(yīng)物、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白組成的組。
2.權(quán)利要求1所述的方法，其中所述的生物標(biāo)志選自α-1-抗胰蛋白酶、AMBP、鈣粒蛋白B、碳酸酐酶、叢生蛋白、肌動(dòng)蛋白絲切蛋白(非肌肉同種型)、ficolin 2、ficolin 3、凝溶膠蛋白、觸珠蛋白、觸珠蛋白-相關(guān)生物標(biāo)志、血紅素蛋白、間-α-胰蛋白酶抑制劑、肽基脯氨酸順?lè)串悩?gòu)酶A、血漿谷胱甘肽過(guò)氧化物酶、血小板堿性蛋白、血清鐵傳遞蛋白、血清淀粉樣A4蛋白、四連接素、運(yùn)甲狀腺素蛋白、玻連蛋白和鋅-α-2-糖蛋白組成的組。
3.用于診斷患者的卵巢癌的方法，所述的方法包括檢測(cè)身體樣品中至少兩種生物標(biāo)志的超表達(dá)，其中檢測(cè)所述生物標(biāo)志的超表達(dá)可特異性鑒定預(yù)示卵巢癌的樣品。
4.權(quán)利要求3所述的方法，其中檢測(cè)所述生物標(biāo)志的超表達(dá)可以將預(yù)示卵巢癌的樣品與預(yù)示良性增殖的樣品區(qū)別開(kāi)來(lái)。
5.權(quán)利要求3所述的方法，其中所述的方法能夠檢測(cè)早期卵巢癌。
6.權(quán)利要求3所述的方法，其中所述的生物標(biāo)志選擇性地在早期卵巢癌中超表達(dá)。
7.權(quán)利要求3所述的方法，其中所述的生物標(biāo)志選自急性期反應(yīng)物、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白組成的組。
8.權(quán)利要求7所述的方法，其中所述的生物標(biāo)志選自α-1-抗胰蛋白酶、AMBP、鈣粒蛋白B、碳酸酐酶、叢生蛋白、肌動(dòng)蛋白絲切蛋白(非肌肉同種型)、ficolin 2、ficolin 3、凝溶膠蛋白、觸珠蛋白、觸珠蛋白-相關(guān)生物標(biāo)志、血紅素蛋白、間-α-胰蛋白酶抑制劑、肽基脯氨酸順?lè)串悩?gòu)酶A、血漿谷胱甘肽過(guò)氧化物酶、血小板堿性蛋白、血清鐵傳遞蛋白、血清淀粉樣A4蛋白、四連接素、運(yùn)甲狀腺素蛋白、玻連蛋白和鋅-α-2-糖蛋白組成的組。
9.權(quán)利要求3所述的方法，其中所述的樣品為血清樣品。
10.權(quán)利要求3所述的方法，其中對(duì)所述生物標(biāo)志超表達(dá)的所述檢測(cè)包括使用抗體檢測(cè)生物標(biāo)志蛋白的表達(dá)。
11.權(quán)利要求3所述的方法，其中對(duì)所述生物標(biāo)志超表達(dá)的所述檢測(cè)包括核酸雜交。
12.用于診斷患者的卵巢癌的方法，所述的方法包括a)從所述的患者中獲得身體樣品；b)使所述的樣品接觸至少一種抗體，其中所述的抗體特異性結(jié)合在卵巢癌中選擇性超表達(dá)的生物標(biāo)志蛋白，并且其中所述的生物標(biāo)志選自急性期反應(yīng)物、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白組成的組；和c)檢測(cè)所述的抗體與所述的生物標(biāo)志蛋白的結(jié)合。
13.權(quán)利要求12所述的方法，其中所述的生物標(biāo)志選自α-1-抗胰蛋白酶、AMBP、鈣粒蛋白B、碳酸酐酶、叢生蛋白、肌動(dòng)蛋白絲切蛋白(非肌肉同種型)、ficolin 2、ficolin 3、凝溶膠蛋白，觸珠蛋白，觸珠蛋白-相關(guān)生物標(biāo)志，血紅素蛋白、間-α-胰蛋白酶抑制劑、肽基脯氨酸順?lè)串悩?gòu)酶A、血漿谷胱甘肽過(guò)氧化物酶、血小板堿性蛋白、血清鐵傳遞蛋白、血清淀粉樣A4蛋白、四連接素、運(yùn)甲狀腺素蛋白、玻連蛋白和鋅-α-2-糖蛋白組成的組。
14.權(quán)利要求12所述的方法，其中所述的抗體為單克隆抗體。
15.用于診斷患者的卵巢癌的方法，所述的方法包括a)從所述的患者中獲得身體樣品；b)使所述的樣品接觸至少兩種抗體，其中所述的抗體各自特異性結(jié)合在卵巢癌中選擇性超表達(dá)的不同生物標(biāo)志蛋白；和c)檢測(cè)所述的抗體與所述的生物標(biāo)志蛋白的結(jié)合。
16.權(quán)利要求15所述的方法，其中所述的生物標(biāo)志選自急性期反應(yīng)物、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白組成的組。
17.權(quán)利要求16所述的方法，其中所述的生物標(biāo)志選自(-1-抗胰蛋白酶、AMBP、鈣粒蛋白B、碳酸酐酶、叢生蛋白、肌動(dòng)蛋白絲切蛋白(非肌肉同種型)、ficolin2、ficolin3、凝溶膠蛋白，觸珠蛋白，觸珠蛋白-相關(guān)生物標(biāo)志，血紅素蛋白、間-α-胰蛋白酶抑制劑、肽基脯氨酸順?lè)串悩?gòu)酶A、血漿谷胱甘肽過(guò)氧化物酶、血小板堿性蛋白、血清鐵傳遞蛋白、血清淀粉樣A蛋白、四連接素、運(yùn)甲狀腺素蛋白、玻連蛋白和鋅-α-2-糖蛋白組成的組。
18.權(quán)利要求15所述的方法，其中所述的抗體作為單獨(dú)的抗體試劑依次或作為抗體混合物同時(shí)與所述的樣品接觸。
19.權(quán)利要求15所述的方法，其中使樣品接觸至少兩種抗體包括使用第一種俘獲抗體和第二種被標(biāo)志的檢測(cè)抗體，其中所述的俘獲抗體和所述的檢測(cè)抗體各自特異性結(jié)合在卵巢癌中選擇性超表達(dá)的生物標(biāo)志蛋白上的不同抗原位點(diǎn)，并且其中將所述的俘獲抗體固定在固相支持體上。
20.試劑盒，包含至少一種抗體，其中所述的抗體特異性結(jié)合在卵巢癌中選擇性超表達(dá)的生物標(biāo)志蛋白，并且其中所述的生物標(biāo)志選自急性期反應(yīng)物、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白組成的組。
21.權(quán)利要求20所述的試劑盒，其中所述的生物標(biāo)志選自α-1-抗胰蛋白酶、AMBP、鈣粒蛋白B、碳酸酐酶、叢生蛋白、肌動(dòng)蛋白絲切蛋白(非肌肉同種型)、ficolin2、ficolin 3、凝溶膠蛋白，觸珠蛋白，觸珠蛋白-相關(guān)生物標(biāo)志，血紅素蛋白、間-α-胰蛋白酶抑制劑、肽基脯氨酸順?lè)串悩?gòu)酶A、血漿谷胱甘肽過(guò)氧化物酶、血小板堿性蛋白、血清鐵傳遞蛋白、血清淀粉樣A蛋白、四連接素、運(yùn)甲狀腺素蛋白、玻連蛋白和鋅-α-2-糖蛋白組成的組。
22.試劑盒，包含至少兩種抗體，其中所述的抗體各自特異性結(jié)合在卵巢癌中選擇性超表達(dá)的生物標(biāo)志蛋白上的不同生物標(biāo)志蛋白。
23.權(quán)利要求22所述的試劑盒，其中該試劑盒包含第一種俘獲抗體和第二種被標(biāo)志的檢測(cè)抗體，其中所述的俘獲抗體和所述的檢測(cè)抗體各自特異性結(jié)合在卵巢癌中選擇性超表達(dá)的生物標(biāo)志蛋白上的不同抗原位點(diǎn)。
全文摘要
提供了用于鑒定患者樣品中的卵巢癌的方法和組合物。本發(fā)明的方法包括檢測(cè)身體樣品中至少一種生物標(biāo)志的超表達(dá)，其中所述的生物標(biāo)志選擇性地在卵巢癌中超表達(dá)。在優(yōu)選的實(shí)施方案中，所述的身體樣品為血清樣品。本發(fā)明的生物標(biāo)志包括在卵巢癌中選擇性超表達(dá)的任何基因或蛋白質(zhì)，包括，例如急性期反應(yīng)物、脂蛋白、調(diào)節(jié)補(bǔ)體系統(tǒng)中涉及的蛋白質(zhì)、編程性細(xì)胞死亡調(diào)節(jié)物、結(jié)合血紅蛋白、血紅素或鐵的蛋白質(zhì)、細(xì)胞結(jié)構(gòu)蛋白、使代謝副產(chǎn)物解毒的酶、生長(zhǎng)因子和激素轉(zhuǎn)運(yùn)蛋白。在本發(fā)明的某些方面中，使用生物標(biāo)志－特異性抗體在蛋白質(zhì)水平上或使用核酸雜交技術(shù)在核酸水平上檢測(cè)所關(guān)注的生物標(biāo)志的超表達(dá)。進(jìn)一步提供了用于實(shí)施本發(fā)明方法的試劑盒。
文檔編號(hào)G01N33/68GK101014862SQ200580027740
公開(kāi)日2007年8月8日 申請(qǐng)日期2005年7月8日 優(yōu)先權(quán)日2004年7月9日
發(fā)明者W·F·小拜爾, T·M·維內(nèi)塔, J·W·格羅克, R·H·布雷修斯 申請(qǐng)人:三路影像公司