人囊性纤维化跨膜电导调节子蛋白的变异模式研究

Mutation Patterns in Human Cystic Fibrosis Transmembrane Conductance Regulator Protein

关键词:  氨基酸对  囊性纤维化  囊性纤维化跨膜电导调节子  变异模式

Key words:  amino-acid pair  cystic fibrosis  cystic fibrosis transmembrane conductance regulator (CFTR)  mutation pattern

摘要:

[目的]编码囊性纤维化跨膜电导调节子(Cystic fibrosis transmembrane conductance regulator,CFTR)蛋白的基因突变可引起囊性纤维化,但该蛋白错义点突变的变异模式尚无报道。[方法]先用氨基酸对可预测性为指标将人CFTR蛋白及其178个错义点突变的氨基酸序列转换成标量序列,然后分析变异前后被替换掉的和替换出的氨基酸对的变化。[结果]97.19%的变异发生在不可预测的氨基酸对;87.08%的变异涉及1个或2个被替换掉的氨基酸对,其实际频率大于预测频率;15.17%的变异带来1个或2个替换出的氨基酸对,它们在正常的CFTR蛋白是不存在的;共有122个变异导致替换出的氨基酸对的实际频率小于预测频率。[结论]不可预测的氨基酸对对变异更敏感,变异的趋势是缩小氨基酸对实际频率和预测频率之间的差距,使氨基酸对的构成更加随机化,而人CFTR蛋白的这种退行性变导致了囊性纤维化。

Abstract:

[Objective] Mutations in the gene that encodes the fibrosis transmembrane conductan-ce regulator (CFTR) protein can cause cystic fibrosis but the patterns of missense mutations in CFTR protein haven't yet been reported.[Methods] The amino-acid pair predictability was used to convert the CFTR protein with its 178 missense mutations into scalar sequences, and then the substituted and substituting amino-acid pairs were analysed before and after mutation.[Results] 97.19% of mutations occurred in unpredictable amino acid pairs.87.08% of mutations targeted one or both substituted amino acid pairs whose actual frequency was larger than their predicted one.15.17% mutations resulted in one or both substituting amino-acid pairs that were absent before mutation.A total of 122 mutations brought about the substituting amino-acid pairs with their actual frequency smaller than predicted one.[Conclusion] The unpredictable amino-acid pairs are more sensitive to mutation, and the mutation trend is to narrow the difference between predicted and actual frequency of amino-acid pairs, thus the composition of amino acid pairs becomes more randomized, which leads the human CFTR protein degenerative and causes cystic fibrosis.