CFTR基因突变与特发性慢性胰腺炎.docx

CFTR基因突变与特发性慢性胰腺炎.docx

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CFTR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

1aattggaagcaaatgacatcacagcaggtcagagaaaaagggttgagcggcaggcaccca

61gagtagtaggtctttggcattaggagcttgagcccagacggccctagcagggaccccagc

121gcccgagagaccatgcagaggtcgcctctggaaaaggccagcgttgtctccaaacttttt

181ttcagctggaccagaccaattttgaggaaaggatacagacagcgcctggaattgtcagac

241atataccaaatcccttctgttgattctgctgacaatctatctgaaaaattggaaagagaa

301tgggatagagagctggcttcaaagaaaaatcctaaactcattaatgcccttcggcgatgt

361tttttctggagatttatgttctatggaatctttttatatttaggggaagtcaccaaagca

421gtacagcctctcttactgggaagaatcatagcttcctatgacccggataacaaggaggaa

481cgctctatcgcgatttatctaggcataggcttatgccttctctttattgtgaggacactg

541ctcctacacccagccatttttggccttcatcacattggaatgcagatgagaatagctatg

601tttagtttgatttataagaagactttaaagctgtcaagccgtgttctagataaaataagt

661attggacaacttgttagtctcctttccaacaacctgaacaaatttgatgaaggacttgca

721ttggcacatttcgtgtggatcgctcctttgcaagtggcactcctcatggggctaatctgg

781gagttgttacaggcgtctgccttctgtggacttggtttcctgatagtccttgcccttttt

841caggctgggctagggagaatgatgatgaagtacagagatcagagagctgggaagatcagt

901gaaagacttgtgattacctcagaaatgattgaaaatatccaatctgttaaggcatactgc

961tgggaagaagcaatggaaaaaatgattgaaaacttaagacaaacagaactgaaactgact

1021cggaaggcagcctatgtgagatacttcaatagctcagccttcttcttctcagggttcttt

1081gtggtgtttttatctgtgcttccctatgcactaatcaaaggaatcatcctccggaaaata

1141ttcaccaccatctcattctgcattgttctgcgcatggcggtcactcggcaatttccctgg

1201gctgtacaaacatggtatgactctcttggagcaataaacaaaatacaggatttcttacaa

1261aagcaagaatataagacattggaatataacttaacgactacagaagtagtgatggagaat

1321gtaacagccttctgggaggagggatttggggaattatttgagaaagcaaaacaaaacaat

1381aacaatagaaaaacttctaatggtgatgacagcctcttcttcagtaatttctcacttctt

1441ggtactcctgtcctgaaagatattaatttcaagatagaaagaggacagttgttggcggtt

1501gctggatccactggagcaggcaagacttcacttctaatggtgattatgggagaactggag

1561ccttcagagggtaaaattaagcacagtggaagaatttcattctgttctcagttttcctgg

1621attatgcctggcaccattaaagaaaatatcatctttggtgtttcctatgatgaatataga

1681tacagaagcgtcatcaaagcatgccaactagaagaggacatctccaagtttgcagagaaa

1741gacaatatagttcttggagaaggtggaatcacactgagtggaggtcaacgagcaagaatt

1801tctttagcaagagcagtatacaaagatgctgatttgtatttattagactctccttttgga

1861tacctagatgttttaacagaaaaagaaatatttgaaagctgtgtctgtaaactgatggct

1921aacaaaactaggattttggtcacttctaaaatggaacatttaaagaaagctgacaaaata

1981ttaattttgcatgaaggtagcagctatttttatgggacattttcagaactccaaaatcta

2041cagccagactttagctcaaaactcatgggatgtgattctttcgaccaatttagtgcagaa

2101agaagaaattcaatcctaactgagaccttacaccgtttctcattagaaggagatgctcct

2161gtctcctggacagaaacaaaaaaacaatcttttaaacagactggagagtttggggaaaaa

2221aggaagaattctattctcaatccaatcaactctatacgaaaattttccattgtgcaaaag

2281actcccttacaaatgaatggcatcgaagaggattctgatgagcctttagagagaaggctg

2341tccttagtaccagattctgagcagggagaggcgatactgcctcgcatcagcgtgatcagc

2401actggccccacgcttcaggcacgaaggaggcagtctgtcctgaacctgatgacacactca

2461gttaaccaaggtcagaacattcaccgaaagacaacagcatccacacgaaaagtgtcactg

2521gcccctcaggcaaacttgactgaactggatatatattcaagaaggttatc

2581tcaagaaactggcttggaaataagtgaagaaattaacgaagaagacttaaaggagtgcttttttgatgat

2641atggagagcataccagcagtgactacatggaacacataccttcgatatattactgtccac

2701aagagcttaatttttgtgctaatttggtgcttagtaatttttctggcagaggtggctgct

2761tctttggttgtgctgtggctccttggaaacactcctcttcaagacaaagggaatagtact

2821catagtagaaataacagctatgcagtgattatcaccagcaccagttcgtattatgtgttt

2881tacatttacgtgggagtagccgacactttgcttgctatgggattcttcagaggtctacca

2941ctggtgcatactctaatcacagtgtcgaaaattttacaccacaaaatgttacattctgtt

3001cttcaagcacctatgtcaaccctcaacacgttgaaagcaggtgggattcttaatagattc

3061tccaaagatatagcaattttggatgaccttctgcctcttaccatatttgacttcatccag

3121ttgttattaattgtgattggagctatagcagttgtcgcagttttacaaccctacatcttt

3181gttgcaacagtgccagtgatagtggcttttattatgttgagagcatatttcctccaaacc

3241tcacagcaactcaaacaactggaatctgaaggcaggagtccaattttcactcatcttgtt

3301acaagcttaaaaggactatggacacttcgtgccttcggacggcagccttactttgaaact

3361ctgttccacaaagctctgaatttacatactgccaactggttcttgtacctgtcaacactg

3421cgctggttccaaatgagaatagaaatgatttttgtcatcttcttcattgctgttaccttc

3481atttccattttaacaacaggagaaggagaaggaagagttggtattatcctgactttagcc

3541atgaatatcatgagtacattgcagtgggctgtaaactccagcatagatgtggatagcttg

3601atgcgatctgtgagccgagtctttaagttcattgacatgccaacagaaggtaaacctacc

3661aagtcaaccaaaccatacaagaatggccaactctcgaaagttatgattattgagaattca

3721cacgtgaagaaagatgacatctggccctcagggggccaaatgactgtcaaagatctcaca

3781gcaaaatacacagaaggtggaaatgccatattagagaacatttccttctcaataagtcct

3841ggccagagggtgggcctcttgggaagaactggatcagggaagagtactttgttatcagct

3901tttttgagactactgaacactgaaggagaaatccagatcgatggtgtgtcttgggattca

3961ataactttgcaacagtggaggaaagcctttggagtgataccacagaaagtatttattttt

4021tctggaacatttagaaaaaacttggatccctatgaacagtggagtgatcaagaaatatgg

4081aaagttgcagatgaggttgggctcagatctgtgatagaacagtttcctgggaagcttgac

4141tttgtccttgtggatgggggctgtgtcctaagccatggccacaagcagttgatgtgcttg

4201gctagatctgttctcagtaaggcgaagatcttgctgcttgatgaacccagtgctcatttg

4261gatccagtaacataccaaataattagaagaactctaaaacaagcatttgctgattgcaca

4321gtaattctctgtgaacacaggatagaagcaatgctggaatgccaacaatttttggtcata

4381gaagagaacaaagtgcggcagtacgattccatccagaaactgctgaacgagaggagcctc

4441ttccggcaagccatcagcccctccgacagggtgaagctctttccccaccggaactcaagc

4501aagtgcaagtctaagccccagattgctgctctgaaagaggagacagaagaagaggtgcaa

4561gatacaaggctttagagagcagcataaatgttgacatgggacatttgctcatggaattgg

4621agctcgtgggacagtcacctcatggaattggagctcgtggaacagttacctctgcctcag

4681aaaacaaggatgaattaagtttttttttaaaaaagaaacatttggtaaggggaattgagg

4741acactgatatgggtcttgataaatggcttcctggcaatagtcaaattgtgtgaaaggtac

4801ttcaaatccttgaagatttaccacttgtgttttgcaagccagattttcctgaaaaccctt

4861gccatgtgctagtaattggaaaggcagctctaaatgtcaatcagcctagttgatcagctt

4921attgtctagtgaaactcgttaatttgtagtgttggagaagaactgaaatcatacttctta

4981gggttatgattaagtaatgataactggaaacttcagcggtttatataagcttgtattcct

5041ttttctctcctctccccatgatgtttagaaacacaactatattgtttgctaagcattcca

5101actatctcatttccaagcaagtattagaataccacaggaaccacaagactgcacatcaaa

5161atatgccccattcaacatctagtgagcagtcaggaaagagaacttccagatcctggaaat

5221cagggttagtattgtccaggtctaccaaaaatctcaatatttcagataatcacaatacat

5281cccttacctgggaaagggctgttataatctttcacaggggacaggatggttcccttgatg

5341aagaagttgatatgccttttcccaactccagaaagtgacaagctcacagacctttgaact

5401agagtttagctggaaaagtatgttagtgcaaattgtcacaggacagcccttctttccaca

5461gaagctccaggtagagggtgtgtaagtagataggccatgggcactgtgggtagacacaca

5521tgaagtccaagcatttagatgtataggttgatggtggtatgttttcaggctagatgtatg

5581tacttcatgctgtctacactaagagagaatgagagacacactgaagaagcaccaatcatg

5641aattagttttatatgcttctgttttataattttgtgaagcaaaattttttctctaggaaa

5701tatttattttaataatgtttcaaacatatataacaatgctgtattttaaaagaatgatta

5761tgaattacatttgtataaaataatttttatatttgaaatattgactttttatggcactag

5821tatttctatgaaatattatgttaaaactgggacaggggagaacctagggtgatattaacc

5881aggggccatgaatcaccttttggtctggagggaagccttggggctgatgcagttgttgcc

5941cacagctgtatgattcccagccagcacagcctcttagatgcagttctgaagaagatggta

6001ccaccagtctgactgtttccatcaagggtacactgccttctcaactccaaactgactctt

6061aagaagactgcattatatttattactgtaagaaaatatcacttgtcaataaaatccatac

6121atttgtgtga

CFTR所对的氨基酸序列

Reversetranslation/OptimizationaccordingtoUniversalcode

ORIGIN

（1  XXXXXXXXXAlaThrGlyCysAlaGlyAlaGlyGlyThrXXXCysGlyCysCysThrCys）

（21 ThrGlyGlyAlaXXXAlaAlaAlaGlyGlyCysCysAlaGlyCysXXXGlyThrThrGly）

（41 ThrCysThrCysCysAlaXXXAlaAlaCysThrThrThrThrThrThrThrXXXCysAla）

（61 GlyCysThrGlyGlyAlaCysCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX）

（81 XXXAlaGlyAlaCysCysAlaAlaThrThrThrXXXThrGlyAlaGlyGlyAlaAlaAla）

（101 GlyGlyXXXAlaThrAlaCysAlaGlyAlaCysAlaGlyXXXCysGlyCysCysThrGly）

（121 GlyAlaAlaThrXXXThrGlyThrCysAlaGlyAlaCysAlaThrXXXAlaThrAlaCys）

（141 CysAlaAlaAlaThrCysXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCys）

（161 CysThrThrCysThrGlyThrThrGlyXXXAlaThrThrCysThrGlyCysThrGlyAla）

（181 XXXCysAlaAlaThrCysThrAlaThrCysThrXXXGlyAlaAlaAlaAlaAlaThrThr）

（201 GlyGlyXXXAlaAlaAlaGlyAlaGlyAlaAlaThrGlyXXXGlyGlyAlaThrAlaGly）

（221 AlaGlyAlaGlyXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCysThrGly）

（241 GlyCysThrThrCysAlaAlaXXXAlaGlyAlaAlaAlaAlaAlaThrCysCysXXXThr）

（261 AlaAlaAlaCysThrCysAlaThrThrXXXAlaAlaThrGlyCysCysCysThrThrCys）

7（281 XXXGlyGlyCysGlyAlaThrGlyThrThrThrXXXThrThrThrCysThrGlyGlyAla）

（301 GlyAlaXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrThrThrAlaThr）

（321 GlyThrThrCysThrXXXAlaThrGlyGlyAlaAlaThrCysThrThrXXXThrThrThr）

（341 AlaThrAlaThrThrThrAlaXXXGlyGlyGlyGlyAlaAlaGlyThrCysAlaXXXCys）

（361 CysAlaAlaAlaGlyCysAlaGlyThrXXXAlaCysAlaGlyCysCysThrCysThrCys）

（381 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXThrThrAlaCysThrGlyGly）

（401 GlyAlaAlaXXXGlyAlaAlaThrCysAlaThrAlaGlyCysXXXThrThrCysCysThr）

（421 AlaThrGlyAlaCysXXXCysCysGlyGlyAlaThrAlaAlaCysAlaXXXAlaGlyGly）

（441 AlaGlyGlyAlaAlaCysGlyXXXCysThrCys