CFTR基因突变与特发性慢性胰腺炎3

1/1CFTR基因突变与特发性慢性胰腺炎ＣＦＴＲ基因突变与特发性慢性胰腺炎生命科学与技术学院生技１１－１班李海文学号：

２０１１１１０３０１５关键词ＣＦＴＲＩＣＰ基因突变发病机制CFTR基因的结构和功能1989年，CFTR基因首次被发现，其位点在第七对常染色体的长臂上(7q31)，其相关基因位于染色体7p基因组DNA的250000对碱基上。

编码产物是由1480个氨基酸组成的～种离子通道蛋白，即囊性纤维化穿膜传导调节因子，它能调节和促进上皮细胞膜电解质离子的转运[z]。

在胰腺，TR分布于导管系统的腔面细胞膜上，为cAMP调控的Cr通道，使Cl一由胰腺导管细胞进入腺泡腔或导管腔，继而导管细胞腔面顶端原浆膜上发生电中性阴离子Cl一和HC0。

一的交换，HCO。

一由细胞内转移至腔内，并带走水分，以利碱化胰液和稀释胰液。

腺泡腔的pH值是酸性的酶原颗粒和导管细胞碱性分泌物动态平衡的结果，腺泡腔正常的pH值可保证腺泡顶端原浆膜正常的酶原颗粒膜内吞和稀释聚集的胰酶[3．4]。

若CFTR功能不足，则腺泡腔的pH值下降，酶原颗粒膜内吞障碍，使腺泡细胞变平，腺泡膨胀，内充满嗜酸性凝结物，直至外分泌功能封闭和含浓缩蛋白质的胰导管阻塞[s]。

Andersen等【6]将正常CFTR基因转染入CF细胞，可恢复正常的Cr转运。

CFTR基因突变CFTR基因突变可分成5类[8]：

①无义、框架移位和拼接突变，导致CFTR蛋白合成的截断和缺乏；②干扰正确的翻译后过程，尽管蛋白本身可能保持正常的功能，但其中大多数不能到达导管细胞顶端原浆膜上；⑧突变致Cl一通道开放，表现为对cAMP刺激反应的减弱，如G551D(甘氨酸在551位点突变为天冬氨酸)；④CFTR的Cl一通道离子选择性和传导性的改变；⑤干扰了正确的转录和翻译，导致功能性CFTR水平降低。

CFTR基因序列1aattggaagcaaatgacatcacagcaggtcagagaaaaagggttgagcggcaggcaccca61gagtagtaggtctttggcattaggagcttgagcccagacggccctagcagggaccccagc121gcccgagagaccatgcagaggtcgcctctggaaaaggccagcgttgtctccaaacttttt181ttcagctggaccagaccaattttgaggaaaggatacagacagcgcctggaattgtcagac241atataccaaatcccttctgttgattctgctgacaatctatctgaaaaattggaaagagaa301tgggatagagagctggcttcaaagaaaaatcctaaactcattaatgcccttcggcgatgt361tttttctggagatttatgttctatggaatctttttatatttaggggaagtcaccaaagca421gtacagcctctcttactgggaagaatcatagcttcctatgacccggataacaaggaggaa481cgctctatcgcgatttatctaggcataggcttatgccttctctttattgtgaggacactg541ctcctacacccagccatttttggccttcatcacattggaatgcagatgagaatagctatg601tttagtttgatttataagaagactttaaagctgtcaagccgtgttctagataaaataagt661attggacaacttgttagtctcctttccaacaacctgaacaaatttgatgaaggacttgca721ttggcacatttcgtgtggatcgctcctttgcaagtggcactcctcatggggctaatctgg781gagttgttacaggcgtctgccttctgtggacttggtttcctgatagtccttgcccttttt841caggctgggctagggagaatgatgatgaagtacagagatcagagagctgggaagatcagt901gaaagacttgtgattacctcagaaatgattgaaaatatccaatctgttaaggcatactgc961tgggaagaagcaatggaaaaaatgattgaaaacttaagacaaacagaactgaaactgact1021cggaaggcagcctatgtgagatacttcaatagctcagccttcttcttctcagggttcttt1081gtggtgtttttatctgtgcttccctatgcactaatcaaaggaatcatcctccggaaaata1141ttcaccaccatctcattctgcattgttctgcgcatggcggtcactcggcaatttccctgg1201gctgtacaaacatggtatgactctcttggagcaataaacaaaatacaggatttcttacaa1261aagcaagaatataagacattggaatataacttaacgactacagaagtagtgatggagaat1321gtaacagccttctgggaggagggatttggggaattatttgagaaagcaaaacaaaacaat1381aacaatagaaaaacttctaatggtgatgacagcctcttcttcagtaatttctcacttctt1441ggtactcctgtcctgaaagatattaatttcaagatagaaagaggacagttgttggcggtt1501gctggatccactggagcaggcaagacttcacttctaatggtgattatgggagaactggag1561ccttcagagggtaaaattaagcacagtggaagaatttcattctgttctcagttttcctgg1621attatgcctggcaccattaaagaaaatatcatctttggtgtttcctatgatgaatataga1681tacagaagcgtcatcaaagcatgccaactagaagaggacatctccaagtttgcagagaaa1741gacaatatagttcttggagaaggtggaatcacactgagtggaggtcaacgagcaagaatt1801tctttagcaagagcagtatacaaagatgctgatttgtatttattagactctccttttgga1861tacctagatgttttaacagaaaaagaaatatttgaaagctgtgtctgtaaactgatggct1921aacaaaactaggattttggtcacttctaaaatggaacatttaaagaaagctgacaaaata1981ttaattttgcatgaaggtagcagctatttttatgggacattttcagaactccaaaatcta2041cagccagactttagctcaaaactcatgggatgtgattctttcgaccaatttagtgcagaa2101agaagaaattcaatcctaactgagaccttacaccgtttctcattagaaggagatgctcct2161gtctcctggacagaaacaaaaaaacaatcttttaaacagactggagagtttggggaaaaa2221aggaagaattctattctcaatccaatcaactctatacgaaaattttccattgtgcaaaag2281actcccttacaaatgaatggcatcgaagaggattctgatgagcctttagagagaaggctg2341tccttagtaccagattctgagcagggagaggcgatactgcctcgcatcagcgtgatcagc2401actggccccacgcttcaggcacgaaggaggcagtctgtcctgaacctgatgacacactca2461gttaaccaaggtcagaacattcaccgaaagacaacagcatccacacgaaaagtgtcactg2521gcccctcaggcaaacttgactgaactggatatatattcaagaaggttatc2581tcaagaaactggcttggaaataagtgaagaaattaacgaagaagacttaaaggagtgcttttttgatgat2641atggagagcataccagcagtgactacatggaacacataccttcgatatattactgtccac2701aagagcttaatttttgtgctaatttggtgcttagtaatttttctggcagaggtggctgct2761tctttggttgtgctgtggctccttggaaacactcctcttcaagacaaagggaatagtact2821catagtagaaataacagctatgcagtgattatcaccagcaccagttcgtattatgtgttt2881tacatttacgtgggagtagccgacactttgcttgctatgggattcttcagaggtctacca2941ctggtgcatactctaatcacagtgtcgaaaattttacaccacaaaatgttacattctgtt3001cttcaagcacctatgtcaaccctcaacacgttgaaagcaggtgggattcttaatagattc3061tccaaagatatagcaattttggatgaccttctgcctcttaccatatttgacttcatccag3121ttgttattaattgtgattggagctatagcagttgtcgcagttttacaaccctacatcttt3181gttgcaacagtgccagtgatagtggcttttattatgttgagagcatatttcctccaaacc3241tcacagcaactcaaacaactggaatctgaaggcaggagtccaattttcactcatcttgtt3301acaagcttaaaaggactatggacacttcgtgccttcggacggcagccttactttgaaact3361ctgttccacaaagctctgaatttacatactgccaactggttcttgtacctgtcaacactg3421cgctggttccaaatgagaatagaaatgatttttgtcatcttcttcattgctgttaccttc3481atttccattttaacaacaggagaaggagaaggaagagttggtattatcctgactttagcc3541atgaatatcatgagtacattgcagtgggctgtaaactccagcatagatgtggatagcttg3601atgcgatctgtgagccgagtctttaagttcattgacatgccaacagaaggtaaacctacc3661aagtcaaccaaaccatacaagaatggccaactctcgaaagttatgattattgagaattca3721cacgtgaagaaagatgacatctggccctcagggggccaaatgactgtcaaagatctcaca3781gcaaaatacacagaaggtggaaatgccatattagagaacatttccttctcaataagtcct3841ggccagagggtgggcctcttgggaagaactggatcagggaagagtactttgttatcagct3901tttttgagactactgaacactgaaggagaaatccagatcgatggtgtgtcttgggattca3961ataactttgcaacagtggaggaaagcctttggagtgataccacagaaagtatttattttt4021tctggaacatttagaaaaaacttggatccctatgaacagtggagtgatcaagaaatatgg4081aaagttgcagatgaggttgggctcagatctgtgatagaacagtttcctgggaagcttgac4141tttgtccttgtggatgggggctgtgtcctaagccatggccacaagcagttgatgtgcttg4201gctagatctgttctcagtaaggcgaagatcttgctgcttgatgaacccagtgctcatttg4261gatccagtaacataccaaataattagaagaactctaaaacaagcatttgctgattgcaca4321gtaattctctgtgaacacaggatagaagcaatgctggaatgccaacaatttttggtcata4381gaagagaacaaagtgcggcagtacgattccatccagaaactgctgaacgagaggagcctc4441ttccggcaagccatcagcccctccgacagggtgaagctctttccccaccggaactcaagc4501aagtgcaagtctaagccccagattgctgctctgaaagaggagacagaagaagaggtgcaa4561gatacaaggctttagagagcagcataaatgttgacatgggacatttgctcatggaattgg4621agctcgtgggacagtcacctcatggaattggagctcgtggaacagttacctctgcctcag4681aaaacaaggatgaattaagtttttttttaaaaaagaaacatttggtaaggggaattgagg4741acactgatatgggtcttgataaatggcttcctggcaatagtcaaattgtgtgaaaggtac4801ttcaaatccttgaagatttaccacttgtgttttgcaagccagattttcctgaaaaccctt4861gccatgtgctagtaattggaaaggcagctctaaatgtcaatcagcctagttgatcagctt4921attgtctagtgaaactcgttaatttgtagtgttggagaagaactgaaatcatacttctta4981gggttatgattaagtaatgataactggaaacttcagcggtttatataagcttgtattcct5041ttttctctcctctccccatgatgtttagaaacacaactatattgtttgctaagcattcca5101actatctcatttccaagcaagtattagaataccacaggaaccacaagactgcacatcaaa5161atatgccccattcaacatctagtgagcagtcaggaaagagaacttccagatcctggaaat5221cagggttagtattgtccaggtctaccaaaaatctcaatatttcagataatcacaatacat5281cccttacctgggaaagggctgttataatctttcacaggggacaggatggttcccttgatg5341aagaagttgatatgccttttcccaactccagaaagtgacaagctcacagacctttgaact5401agagtttagctggaaaagtatgttagtgcaaattgtcacaggacagcccttctttccaca5461gaagctccaggtagagggtgtgtaagtagataggccatgggcactgtgggtagacacaca5521tgaagtccaagcatttagatgtataggttgatggtggtatgttttcaggctagatgtatg5581tacttcatgctgtctacactaagagagaatgagagacacactgaagaagcaccaatcatg5641aattagttttatatgcttctgttttataattttgtgaagcaaaattttttctctaggaaa5701tatttattttaataatgtttcaaacatatataacaatgctgtattttaaaagaatgatta5761tgaattacatttgtataaaataatttttatatttgaaatattgactttttatggcactag5821tatttctatgaaatattatgttaaaactgggacaggggagaacctagggtgatattaacc5881aggggccatgaatcaccttttggtctggagggaagccttggggctgatgcagttgttgcc5941cacagctgtatgattcccagccagcacagcctcttagatgcagttctgaagaagatggta6001ccaccagtctgactgtttccatcaagggtacactgccttctcaactccaaactgactctt6061aagaagactgcattatatttattactgtaagaaaatatcacttgtcaataaaatccatac6121atttgtgtgaCFTR所对的氨基酸序列Reversetranslation/OptimizationaccordingtoUniversalcodeORIGIN(1XXXXXXXXXAlaThrGlyCysAlaGlyAlaGlyGlyThrXXXCysGlyCysCysThrCys)(21ThrGlyGlyAlaXXXAlaAlaAlaGlyGlyCysCysAlaGlyCysXXXGlyThrThrGly)(41ThrCysThrCysCysAlaXXXAlaAlaCysThrThrThrThrThrThrThrXXXCysAla)(61GlyCysThrGlyGlyAlaCysCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(81XXXAlaGlyAlaCysCysAlaAlaThrThrThrXXXThrGlyAlaGlyGlyAlaAlaAla)(101GlyGlyXXXAlaThrAlaCysAlaGlyAlaCysAlaGlyXXXCysGlyCysCysThrGly)(121GlyAlaAlaThrXXXThrGlyThrCysAlaGlyAlaCysAlaThrXXXAlaThrAlaCys)(141CysAlaAlaAlaThrCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCys)(161CysThrThrCysThrGlyThrThrGlyXXXAlaThrThrCysThrGlyCysThrGlyAla)(181XXXCysAlaAlaThrCysThrAlaThrCysThrXXXGlyAlaAlaAlaAlaAlaThrThr)(201GlyGlyXXXAlaAlaAlaGlyAlaGlyAlaAlaThrGlyXXXGlyGlyAlaThrAlaGly)(221AlaGlyAlaGlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCysThrGly)(241GlyCysThrThrCysAlaAlaXXXAlaGlyAlaAlaAlaAlaAlaThrCysCysXXXThr)(261AlaAlaAlaCysThrCysAlaThrThrXXXAlaAlaThrGlyCysCysCysThrThrCys)7(281XXXGlyGlyCysGlyAlaThrGlyThrThrThrXXXThrThrThrCysThrGlyGlyAla)(301GlyAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrThrThrAlaThr)(321GlyThrThrCysThrXXXAlaThrGlyGlyAlaAlaThrCysThrThrXXXThrThrThr)(341AlaThrAlaThrThrThrAlaXXXGlyGlyGlyGlyAlaAlaGlyThrCysAlaXXXCys)(361CysAlaAlaAlaGlyCysAlaGlyThrXXXAlaCysAlaGlyCysCysThrCysThrCys)(381XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrThrAlaCysThrGlyGly)(401GlyAlaAlaXXXGlyAlaAlaThrCysAlaThrAlaGlyCysXXXThrThrCysCysThr)(421AlaThrGlyAlaCysXXXCysCysGlyGlyAlaThrAlaAlaCysAlaXXXAlaGlyGly)(441AlaGlyGlyAlaAlaCysGlyXXXCysThrCysThrAlaThrCysGlyCysGlyXXXXXX)(461XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaThrThrThrAlaThrCysThrAla)1(481GlyXXXGlyCysAlaThrAlaGlyGlyCysThrThrXXXAlaThrGlyCysCysThrThr)(501CysThrCysXXXThrThrThrAlaThrThrGlyThrGlyAlaXXXGlyGlyAlaCysAla)(521CysThrGlyCysThrXXXCysCysThrAlaCysAlaCysCysCysAlaXXXXXXXXXXXX)(541XXXXXXXXXXXXXXXXXXXXXXXXXXXGlyCysCysAlaThrThrThrThrThrGlyXXX)(561GlyCysCysThrThrCysAlaThrCysAlaXXXCysAlaThrThrGlyGlyAlaAlaThr)(581GlyXXXCysAlaGlyAlaThrGlyAlaGlyAlaAlaXXXThrAlaGlyCysThrAlaThr)(601GlyThrThrXXXThrAlaGlyThrThrThrGlyAlaThrThrXXXXXXXXXXXXXXXXXX)(621XXXXXXXXXXXXXXXXXXXXXThrAlaThrAlaAlaGlyAlaAlaGlyAlaXXXCysThr)(641ThrThrAlaAlaAlaGlyCysThrXXXGlyThrCysAlaAlaGlyCysCysGlyThrXXX)(661GlyThrThrCysThrAlaGlyAlaThrAlaXXXAlaAlaAlaThrAlaAlaGlyThrAla)(681ThrXXXThrGlyGlyAlaCysAlaAlaCysThrThrXXXXXXXXXXXXXXXXXXXXXXXX)(701XXXXXXXXXXXXXXXGlyThrThrAlaGlyThrCysThrCysCysXXXThrThrThrCys)(721CysAlaAlaCysAlaAlaXXXCysCysThrGlyAlaAlaCysAlaAlaAlaXXXThrThr)(741ThrGlyAlaThrGlyAlaAlaGlyXXXGlyAlaCysThrThrGlyCysAlaThrThrXXX)(761GlyGlyCysAlaCysAlaThrThrThrCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(781XXXXXXXXXGlyThrGlyThrGlyGlyAlaThrCysGlyXXXCysThrCysCysThrThr)(801ThrGlyCysAlaXXXAlaGlyThrGlyGlyCysAlaCysThrCysXXXCysThrCysAla)(821ThrGlyGlyGlyGlyCysXXXThrAlaAlaThrCysThrGlyGlyGlyAlaXXXGlyThr)(841ThrGlyThrThrAlaCysAlaGlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(861XXXGlyCysGlyThrCysThrGlyCysCysThrXXXThrCysThrGlyThrGlyGlyAla)(881CysThrXXXThrGlyGlyThrThrThrCysCysThrGlyXXXAlaThrAlaGlyThrCys)(901CysThrThrGlyXXXCysCysCysThrThrThrThrThrCysAlaXXXGlyGlyCysThr)(921GlyGlyGlyCysThrAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXGly)(941GlyGlyAlaGlyAlaAlaThrGlyAlaXXXThrGlyAlaThrGlyAlaAlaGlyThrAla)(961XXXCysAlaGlyAlaGlyAlaThrCysAlaGlyXXXAlaGlyAlaGlyCysThrGlyGly)(981GlyAlaXXXAlaGlyAlaThrCysAlaGlyThrGlyAlaXXXAlaAlaGlyAlaCysThr)(1001ThrGlyThrGlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaThrThr)(1021AlaCysCysThrCysAlaGlyXXXAlaAlaAlaThrGlyAlaThrThrGlyAlaXXXAla)(1041AlaAlaThrAlaThrCysCysAlaAlaXXXThrCysThrGlyThrThrAlaAlaGlyGly)(1061XXXCysAlaThrAlaCysThrGlyCysThrGlyXXXGlyGlyAlaAlaGlyAlaAlaGly)(1081CysAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaThrGlyGlyAla)(1101AlaAlaAlaAlaAlaXXXThrGlyAlaThrThrGlyAlaAlaAlaAlaXXXCysThrThr)(1121AlaAlaGlyAlaCysAlaAlaXXXAlaCysAlaGlyAlaAlaCysThrGlyAlaXXXAla)(1141AlaCysThrGlyAlaCysThrCysGlyXXXGlyAlaAlaGlyGlyCysAlaGlyCysCys)(1161XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrAlaThrGlyThrGlyAla)(1181GlyAlaThrXXXAlaCysThrThrCysAlaAlaThrAlaGlyXXXCysThrCysAlaGly)(1201CysCysThrThrCysXXXThrThrCysThrThrCysThrCysAlaGlyXXXGlyGlyThr)(1221ThrCysThrThrThrGlyThrXXXGlyGlyThrGlyThrThrThrThrThrAlaXXXXXX)(1241XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrCysThrGlyThrGlyCysThrThr)(1261CysXXXCysCysThrAlaThrGlyCysAlaCysThrXXXAlaAlaThrCysAlaAlaAla)(1281GlyGlyAlaXXXAlaThrCysAlaThrCysCysThrCysCysXXXGlyGlyAlaAlaAla)(1301AlaThrAlaThrThrXXXCysAlaCysCysAlaCysCysAlaThrCysXXXXXXXXXXXX)(1321XXXXXXXXXXXXXXXXXXXXXXXXXXXThrCysAlaThrThrCysThrGlyCysAlaXXX)(1341ThrThrGlyThrThrCysThrGlyCysGlyXXXCysAlaThrGlyGlyCysGlyGlyThr)(1361CysXXXAlaCysThrCysGlyGlyCysAlaAlaThrXXXThrThrCysCysCysThrGly)(1381GlyGlyCysXXXThrGlyThrAlaCysAlaAlaAlaCysAlaXXXXXXXXXXXXXXXXXX)(1401XXXXXXXXXXXXXXXXXXXXXThrGlyGlyThrAlaThrGlyAlaCysThrXXXCysThr)(1421CysThrThrGlyGlyAlaGlyCysXXXAlaAlaThrAlaAlaAlaCysAlaAlaAlaXXX)(1441AlaThrAlaCysAlaGlyGlyAlaThrThrXXXThrCysThrThrAlaCysAlaAlaAla)(1461AlaXXXGlyCysAlaAlaGlyAlaAlaThrAlaThrXXXXXXXXXXXXXXXXXXXXXXXX)(1481XXXXXXXXXXXXXXXAlaAlaGlyAlaCysAlaThrThrGlyGlyXXXAlaAlaThrAla)(1501ThrAlaAlaCysThrThrXXXAlaAlaCysGlyAlaCysThrAlaCysAlaXXXGlyAla)(1521AlaGlyThrAlaGlyThrGlyAlaXXXThrGlyGlyAlaGlyAlaAlaThrGlyThrXXX)G(1541AlaAlaCysAlaGlyCysCysThrThrCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(1561XXXXXXXXXThrGlyGlyGlyAlaGlyGlyAlaGlyGlyXXXGlyAlaThrThrThrGly)(1581GlyGlyGlyAlaXXXAlaThrThrAlaThrThrThrGlyAlaGlyXXXAlaAlaAlaGly)T(1601CysAlaAlaAlaAlaCysXXXAlaAlaAlaAlaCysAlaAlaThrAlaAlaXXXCysAla)(1621AlaThrAlaGlyAlaAlaAlaAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(1641XXXAlaCysThrThrCysThrAlaAlaThrGlyXXXGlyThrGlyAlaThrGlyAlaCys)(1661AlaGlyXXXCysCysThrCysThrThrCysThrThrCysXXXAlaGlyThrAlaAlaThr)(1681ThrThrCysThrXXXCysAlaCysThrThrCysThrThrGlyGlyXXXThrAlaCysThr)(1701CysCysThrGlyThrCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCys)(1721ThrGlyAlaAlaAlaGlyAlaThrAlaXXXThrThrAlaAlaThrThrThrCysAlaAla)(1741XXXGlyAlaThrAlaGlyAlaAlaAlaGlyAlaXXXGlyGlyAlaCysAlaGlyThrThr)G(1761GlyThrXXXThrGlyGlyCysGlyGlyThrThrGlyCysXXXThrGlyGlyAlaThrCys)(1781CysAlaCysThrXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXGlyGlyAla)(1801GlyCysAlaGlyGlyCysAlaXXXAlaGlyAlaCysThrThrCysAlaCysThrXXXThr)(1821CysThrAlaAlaThrGlyGlyThrGlyXXXAlaThrThrAlaThrGlyGlyGlyAlaGly)G(1841XXXAlaAlaCysThrGlyGlyAlaGlyCysCysXXXThrThrCysAlaGlyAlaGlyGly)(1861GlyThrXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaAlaAlaAlaThr)(1881ThrAlaAlaGlyCysXXXAlaCysAlaGlyThrGlyGlyAlaAlaGlyXXXAlaAlaThr)(1901ThrThrCysAlaThrThrCysXXXThrGlyThrThrCysThrCysAlaGlyThrXXXThr)(1921ThrThrCysCysThrGlyGlyAlaThrXXXThrAlaThrGlyCysCysThrGlyGlyCys)(1941XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaCysCysAlaThrThrAla)(1961AlaAlaGlyXXXAlaAlaAlaAlaThrAlaThrCysAlaThrXXXCysGlyGlyThrGly)(1981ThrThrThrCysCysXXXThrAlaThrGlyAlaThrGlyAlaAlaThrXXXAlaThrAla)(2001GlyAlaThrAlaCysAlaGlyXXXAlaAlaGlyCysGlyThrCysAlaThrCysXXXXXX)(2021XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaAlaAlaGlyCysAlaThrGlyCys)(2041CysXXXAlaAlaCysThrAlaGlyAlaAlaGlyAlaXXXGlyGlyAlaCysAlaThrCys)(2061ThrCysCysXXXAlaAlaGlyThrThrThrGlyCysAlaGlyXXXAlaGlyAlaAlaAla)(2081GlyAlaCysAlaAlaXXXThrAlaThrAlaGlyThrThrCysThrThrXXXXXXXXXXXX)(2101XXXXXXXXXXXXXXXXXXXXXXXXXXXGlyGlyAlaGlyAlaAlaGlyGlyThrGlyXXX)(2121GlyAlaAlaThrCysAlaCysAlaCysThrXXXGlyAlaGlyThrGlyGlyAlaGlyGly)(2141ThrXXXCysAlaAlaCysGlyAlaGlyCysAlaAlaXXXGlyAlaAlaThrThrThrCys)(2161ThrThrThrXXXAlaGlyCysAlaAlaGlyAlaGlyCysAlaXXXXXXXXXXXXXXXXXX)(2181XXXXXXXXXXXXXXXXXXXXXGlyThrAlaThrAlaCysAlaAlaAlaGlyXXXAlaThr)(2201GlyCysThrGlyAlaThrThrThrXXXGlyThrAlaThrThrThrAlaThrThrAlaXXX)(2221GlyAlaCysThrCysThrCysCysThrThrXXXThrThrGlyGlyAlaThrAlaCysCys)(2241ThrXXXAlaGlyAlaThrGlyThrThrThrThrAlaXXXXXXXXXXXXXXXXXXXXXXXX)(2261XXXXXXXXXXXXXXXAlaCysAlaGlyAlaAlaAlaAlaAlaGlyXXXAlaAlaAlaThr)(2281AlaThrThrThrGlyAlaXXXAlaAlaGlyCysThrGlyThrGlyThrCysXXXThrGly)(2301ThrAlaAlaAlaCysThrGlyAlaXXXThrGlyGlyCysThrAlaAlaCysAlaAlaXXX)(2321AlaAlaCysThrAlaGlyGlyAlaThrThrXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(2341XXXXXXXXXThrThrGlyGlyThrCysAlaCysThrThrXXXCysThrAlaAlaAlaAla)(2361ThrGlyGlyAlaXXXAlaCysAlaThrThrThrAlaAlaAlaGlyXXXAlaAlaAlaGly)(2381CysThrGlyAlaCysAlaXXXAlaAlaAlaThrAlaThrThrAlaAlaThrXXXThrThr)(2401ThrGlyCysAlaThrGlyAlaAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(2421XXXXXXGlyGlyThrAlaGlyCysAlaGlyCysThrXXXAlaThrThrThrThrThrAla)(2441ThrGlyGlyXXXGlyAlaCysAlaThrThrThrThrCysAlaXXXGlyAlaAlaCysThr)(2461CysCysAlaAlaAlaXXXAlaThrCysThrAlaCysAlaGlyCysCysXXXAlaGlyAla)(2481CysThrThrThrAlaGlyCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(2501XXXThrCysAlaAlaAlaAlaCysThrCysAlaXXXThrGlyGlyGlyAlaThrGlyThr)(2521GlyAlaXXXThrThrCysThrThrThrCysGlyAlaCysXXXCysAlaAlaThrThrThr)(2541AlaGlyThrGlyXXXCysAlaGlyAlaAlaAlaGlyAlaAlaGlyXXXAlaAlaAlaThr)G(2561ThrCysAlaAlaThrCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(2581CysThrAlaAlaCysThrGlyAlaGlyAlaXXXCysCysThrThrAlaCysAlaCysCys)(2601GlyXXXThrThrThrCysThrCysAlaThrThrAlaXXXGlyAlaAlaGlyGlyAlaGly)G(2621AlaThrGlyXXXCysThrCysCysThrGlyThrCysThrCysXXXCysThrGlyGlyAla)(2641CysAlaGlyAlaAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaCys)(2661AlaAlaAlaAlaAlaAlaAlaCysXXXAlaAlaThrCysThrThrThrThrAlaAlaXXX)(2681AlaCysAlaGlyAlaCysThrGlyGlyAlaXXXGlyAlaGlyThrThrThrGlyGlyGly)T(2701GlyXXXAlaAlaAlaAlaAlaAlaGlyGlyAlaAlaXXXGlyAlaAlaThrThrCysThr)C(2721AlaThrThrXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCysThrCysAla)(2741AlaThrCysCysAlaAlaXXXThrCysAlaAlaCysThrCysThrAlaThrXXXAlaCys)(2761GlyAlaAlaAlaAlaThrThrThrXXXThrCysCysAlaThrThrGlyThrGlyCysXXX)(2781AlaAlaAlaAlaGlyAlaCysThrCysCysXXXCysThrThrAlaCysAlaAlaAlaThr)(2801GlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaAlaThrGlyGlyCys)(2821AlaThrCysGlyXXXAlaAlaGlyAlaGlyGlyAlaThrThrCysXXXThrGlyAlaThr)(2841GlyAlaGlyCysCysThrXXXThrThrAlaGlyAlaGlyAlaGlyAlaAlaXXXGlyGly)G(2861CysThrGlyThrCysCysThrThrXXXAlaGlyThrAlaCysCysAlaGlyAlaThrXXX)(2881XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrCysThrGlyAlaGlyCysAla)(2901GlyGlyXXXGlyAlaGlyAlaGlyGlyCysGlyAlaThrXXXAlaCysThrGlyCysCys)(2921ThrCysGlyCysXXXAlaThrCysAlaGlyCysGlyThrGlyAlaXXXThrCysAlaGly)(2941CysAlaCysThrGlyGlyXXXCysCysCysCysAlaCysGlyCysThrThrXXXXXXXXX)(2961XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCysAlaGlyGlyCysAlaCysGlyAlaAla)(2981XXXGlyGlyAlaGlyGlyCysAlaGlyThrCysXXXThrGlyThrCysCysThrGlyAla)(3001AlaCysXXXCysThrGlyAlaThrGlyAlaCysAlaCysXXXAlaCysThrCysAlaGly)(3021ThrThrAlaAlaXXXCysCysAlaAlaGlyGlyThrCysAlaGlyXXXXXXXXXXXXXXX)(3041XXXXXXXXXXXXXXXXXXXXXXXXAlaAlaCysAlaThrThrCysAlaCysCysXXXGly)(3061AlaAlaAlaGlyAlaCysAlaAlaCysXXXAlaGlyCysAlaThrCysCysAlaCysAla)(3081XXXCysGlyAlaAlaAlaAlaGlyThrGlyThrXXXCysAlaCysThrGlyGlyCysCys)(3101CysCysXXXThrCysAlaGlyGlyCysAlaAlaAlaCysXXXXXXXXXXXXXXXXXXXXX)(3121XXXXXXXXXXXXXXXXXXThrThrGlyAlaCysThrGlyAlaAlaCysXXXThrGlyGly)(3141AlaThrAlaThrAlaThrAlaXXXThrThrCysAlaAlaGlyAlaAlaGlyGlyXXXThr)(3161ThrAlaThrCysThrCysAlaAlaGlyXXXAlaAlaAlaCysThrGlyGlyCysThrThr)(3181XXXGlyGlyAlaAlaAlaThrAlaAlaGlyThrXXXXXXXXXXXXXXXXXXXXXXXXXXX)(3201XXXXXXXXXXXXGlyAlaAlaGlyAlaAlaAlaThrThrAlaXXXAlaCysGlyAlaAla)(3221GlyAlaAlaGlyAlaXXXCysThrThrAlaAlaAlaGlyGlyAlaGlyXXXThrGlyCys)T(3241ThrThrThrThrThrThrGlyXXXAlaThrGlyAlaThrAlaThrGlyGlyAlaXXXGly)(3261AlaGlyCysAlaThrAlaCysCysAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(3281XXXXXXGlyCysAlaGlyThrGlyAlaCysThrAlaXXXCysAlaThrGlyGlyAlaAla)(3301CysAlaCysXXXAlaThrAlaCysCysThrThrCysGlyAlaXXXThrAlaThrAlaThr)(3321ThrAlaCysThrGlyXXXThrCysCysAlaCysAlaAlaGlyAlaGlyXXXXXXXXXXXX)(3341XXXXXXXXXXXXXXXXXXXXXXXXXXXCysThrThrAlaAlaThrThrThrThrThrXXX)(3361GlyThrGlyCysThrAlaAlaThrThrThrXXXGlyGlyThrGlyCysThrThrAlaGly)(3381ThrXXXAlaAlaThrThrThrThrThrCysThrGlyXXXGlyCysAlaGlyAlaGlyGly)(3401ThrGlyGlyXXXCysThrGlyCysThrThrCysThrThrThrXXXGlyGlyThrThrGly)(3421ThrGlyCysThrGlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrGly)(3441GlyCysThrCysCysThrThrGlyXXXGlyAlaAlaAlaCysAlaCysThrCysCysXXX)(3461ThrCysThrThrCysAlaAlaGlyAlaCysXXXAlaAlaAlaGlyGlyGlyAlaAlaThr)(3481AlaXXXGlyThrAlaCysThrCysAlaThrAlaGlyXXXThrAlaGlyAlaAlaAlaThr)(3501AlaAlaCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaGlyCysThr)(3521AlaThrGlyCysAlaGlyXXXThrGlyAlaThrThrAlaThrCysAlaCysXXXCysAla)(3541GlyCysAlaCysCysAlaGlyThrXXXThrCysGlyThrAlaThrThrAlaThrGlyXXX)(3561ThrGlyThrThrThrThrAlaCysAlaThrXXXThrThrAlaCysGlyThrGlyGlyGly)(3581AlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXGlyThrAlaGlyCysCys)(3601GlyAlaCysAlaXXXCysThrThrThrGlyCysThrThrGlyCysXXXThrAlaThrGly)(3621GlyGlyAlaThrThrCysXXXThrThrCysAlaGlyAlaGlyGlyThrCysXXXThrAla)(3641CysCysAlaCysThrGlyGlyThrXXXGlyCysAlaThrAlaCysThrCysThrAlaXXX)(3661XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaThrCysAlaCysAlaGlyThr)(3681GlyThrXXXCysGlyAlaAlaAlaAlaThrThrThrThrXXXAlaCysAlaCysCysAla)(3701CysAlaAlaAlaXXXAlaThrGlyThrThrAlaCysAlaThrThrXXXCysThrGlyThr)(3721ThrCysThrThrCysAlaXXXAlaGlyCysAlaCysCysThrAlaThrGlyXXXXXXXXX)(3741XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrCysAlaAlaCysCysCysThrCysAla)(3761XXXAlaCysAlaCysGlyThrThrGlyAlaAlaXXXAlaGlyCysAlaGlyGlyThrGly)(3781GlyGlyXXXAlaThrThrCysThrThrAlaAlaThrAlaXXXGlyAlaThrThrCysThr)(3801CysCysAlaAlaXXXAlaGlyAlaThrAlaThrAlaGlyCysAlaXXXXXXXXXXXXXXX)(3821XXXXXXXXXXXXXXXXXXXXXXXXAlaThrThrThrThrGlyGlyAlaThrGlyXXXAla)(3841CysCysThrThrCysThrGlyCysCysXXXThrCysThrThrAlaCysCysAlaThrAla)(3861XXXThrThrThrGlyAlaCysThrThrCysAlaXXXThrCysCysAlaGlyThrThrGly)(3881ThrThrXXXAlaThrThrAlaAlaThrThrGlyThrGlyXXXXXXXXXXXXXXXXXXXXX)(3901XXXXXXXXXXXXXXXXXXAlaThrThrGlyGlyAlaGlyCysThrAlaXXXThrAlaGly)(3921CysAlaGlyThrThrGlyThrXXXCysGlyCysAlaGlyThrThrThrThrAlaXXXCys)(3941AlaAlaCysCysCysThrAlaCysAlaXXXThrCysThrThrThrGlyThrThrGlyCys)(3961XXXAlaAlaCysAlaGlyThrGlyCysCysAlaXXXXXXXXXXXXXXXXXXXXXXXXXXX)(3981XXXXXXXXXXXXGlyThrGlyAlaThrAlaGlyThrGlyGlyXXXCysThrThrThrThr)(4001AlaThrThrAlaThrXXXGlyThrThrGlyAlaGlyAlaGlyCysAlaXXXThrAlaThr)(4021ThrThrCysCysThrCysCysXXXAlaAlaAlaCysCysThrCysAlaCysAlaXXXGly)(4041CysAlaAlaCysThrCysAlaAlaAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(4061XXXXXXCysAlaAlaCysThrGlyGlyAlaAlaThrXXXCysThrGlyAlaAlaGlyGly)(4081CysAlaGlyXXXGlyAlaGlyThrCysCysAlaAlaThrThrXXXThrThrCysAlaCys)12241TGCGCGGGGTAGGGTGCTGGCACATGTTGCGCCGCAACGACTTGAACCACATGTGCGTGC(4101ThrCysAlaThrCysXXXThrThrGlyThrThrAlaCysAlaAlaGlyXXXCysThrThr)(4121AlaAlaAlaAlaGlyGlyAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX)(4141CysThrAlaThrGlyGlyAlaCysAlaCysXXXThrThrCysGlyThrGlyCysCysThr)(4161ThrXXXCysGlyGlyAlaCysGlyGlyCysAlaGlyXXXCysCysThrThrAlaCysThr)(4181ThrThrGlyXXXAlaAlaAlaCysThrCysThrGlyThrThrXXXCysCysAlaCysAla)(4201AlaAlaGlyCysThrXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCysThr)(4221GlyAlaAlaThrThrThrAlaCysXXXAlaThrAlaCysThrGlyCysCysAlaAlaXXX)(4241CysThrGlyGlyThrThrCysThrThrGlyXXXThrAlaCysCysThrGlyThrCysAla)(4261AlaXXXCysAlaCysThrGlyCysGlyCysThrGlyXXXGlyThrThrCysCysAlaAla)(4281AlaThrGlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaGlyAlaAla)(4301ThrAlaGlyAlaAlaAlaXXXThrGlyAlaThrThrThrThrThrGlyThrXXXCysAla)(4321ThrCysThrThrCysThrThrCysXXXAlaThrThrGlyCysThrGlyThrThrAlaXXX)(4341CysCysThrThrCysAlaThrThrThrCysXXXCysAlaThrThrThrThrAlaAlaCys)(4361AlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaCysAlaGlyGlyAla)(4381GlyAlaAlaGlyXXXGlyAlaGlyAlaAlaGlyGlyAlaAlaGlyXXXAlaGlyThrThr)(4401GlyGlyThrAlaThrThrXXXAlaThrCysCysThrGlyAlaCysThrThrXXXThrAla)(4421GlyCysCysAlaThrGlyAlaAlaXXXThrAlaThrCysAlaThrGlyAlaGlyThrXXX)(4441XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXAlaCysAlaThrThrGlyCysAla)(4461GlyThrXXXGlyGlyGlyCysThrGlyThrAlaAlaAlaXXXCysThrCysCysAlaGly)(4481CysAlaThrAlaXXXGlyAlaThrGlyThrGlyGlyAlaThrAlaXXXGlyCysThrThr)(4501GlyAlaThrGlyCysGlyXXXAlaThrCysThrGlyThrGlyAlaGlyCysXXXXXXXXX)(4521XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCysGlyAlaGlyThrCysThrThrThrAla)(4541XXXAlaGlyThrThrCysAlaThrThrGlyAlaXXXCysAlaThrGlyCysCysAlaAla)(4561CysAlaXXXGlyAlaAlaGlyGlyThrAlaAlaAlaCysXXXCysThrAlaCysCysAla)(4581AlaGlyThrCysXXXAlaAlaCysCysAlaAlaAlaCysCysAlaXXXXXXXXXXXXXXX)(4601XXXXXXXXXXXXXXXXXXXXXXXXThrAlaCysAlaAlaGlyAlaAlaThrGlyXXXGly)(4621CysCysAlaAlaCysThrCysThrCysXXXGlyAlaAlaAlaGlyThrThrAlaThrGly)(4641XXXAlaThrThrAlaThrThrGlyAlaGlyAlaXXXAlaThrThrCys