SLC26A4基因频发致聋突变的种族差异及其分子结构分析

Study on molecular structure and racial difference of high frequency pathological SLC26A4 mutations in hearing loss

目的 ：SLC26A4基因是导致遗传性耳聋的第二个常见致病基因,在已知耳聋患者中SLC26A4基因突变至少有170种。然而不同地区的耳聋人群突变热点各异,更无SLC26A4致聋性频发突变频率的相关报道,因此本研究对致聋基因SLC26A4频发突变的种族差异及其分子结构进行了深入探讨。方法：依据公共数据库,系统收集1997-2014年全球SLC26A4与耳聋相关的文献报道662篇,基于NEWCASTLE OTTAWA（NOS）标准筛选出31篇文献纳入研究,采用STATA11.2和Rev Man 5.1软件进行了Meta分析,并结合Swiss Model软件对SLC26A4频发致聋突变而导致的蛋白分子结构变异进行比较分析。结果：1发现SLC26A4突变增加耳聋发病风险（OR=39.73,95%CI：21.36-73.90,P〈0.001）;2 SLC26A4突变在亚洲人群中有显著异质性,而欧美地区则无异质性;3鉴定出SLC26A4基因6种高频致聋突变（p.V138F、p.G209V、c.IVS7-2A〉G、c.IVS8＋1G〉A、p.T416P和p.H723R）,并通过蛋白质分子结构模拟发现突变后有意义的结构改变。结论 ：本研究为SCL26A4致聋突变在不同地区耳聋人群中的遗传学效应研究奠定了基础。

Objective：TSLC26A4 gene is thought to be the second major contributor to hereditary hearing loss. At least 170 pathological mutations of SLC26A4 were identified in deafness patients,and showed regional differences and ethnic specificity for different groups around the world. However,no unanimous conclusion was achieved on the high frequency mutations of SLC26A4 which induced the hearing loss. This study is aimed to invistigate the molecular structure and racial difference of high frequency pathological SLC26A4 mutations in hearing loss. Methods： Total of 662 published epidemiological studies of SLC26A4 mutation and deafness was collected from 1997,Jan to 2014,Dec. through the databases. Based on the NOS standard,31 of the articles were included. meta-analysis was carried to study the data of SLC26A4 mutation frequency. Stata11.2 and Rev Man 5.1 software was used to describe the data of literature for meta-analysis to explore deaf risk correlation. Swiss Model software was used to analyze the molecular structure of high frequency pathological SLC26A4 mutations. Results： 1 A variety of types of SLC26A4 mutations are associated with an increased deafness risk（OR = 39.73,95% CI： 21.359-73.903,P 0.0001）; 2 It indicates the significant heterogeneity in Asian but not in European and American; 3Particularly,the 6 kinds of mutations were calculated as high frequency pathological SLC26A4 mutations（p.V138 F,p.G209 V,IVS7-2AG,IVS8＋1GA,p.T416 P and p.H723R）,protein structure changes of which were simulated by Swiss Model. Conclusion： These findings advance our knowledge of the genetic basis of SCL26A4 variation with hereditary hearing loss in the multiethnic populations