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.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
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- CFTR 基因突变 特发性 慢性 胰腺炎