常染色体显性低频感音神经性耳聋一家系MYO7A基因一个新突变位点的鉴定分析

Identification of a novel mutation in MYO7A gene in a Chinese family with autosamal dominant low-frequency sensorineural hearing loss

目的一个命名为HB-S037的常染色体显性非综合征遗传性耳聋中国家系致病基因定位及MYO7A基因突变分析。方法通过对该家系参与连锁分析的23名成员应用Affymetrix5.0SNP(Single Nucleotide Polymorphisms,单核苷酸多态性)芯片进行全基因组扫描及连锁分析,致病基因的染色体定位;之后,选取微卫星标记进行精细扫描,确定候选基因,MYO7A基因外显子扩增及测序。结果应用Affymetrix 5.0 SNP芯片进行全基因组扫描及连锁分析,将HB-S037家系的致病基因初步定位于第11号染色体11q13.4-14.1之间(最大LOD值=4.346),选取初步定位区域内及附近的12个微卫星标记进行精细定位及单倍型分析,将致病基因定位于微卫星标记D11S1314和D11S4166之间的区域(最大LOD值=4.18)。对定位区域内候选基因MY07A的49个外显子直接测序,在MYO7A第17外显子有一个新的突变位点c.2011G>A,该位点突变与此家系疾病表型共分离,并引起编码第671位的甘氨酸替换为丝氨酸(G671S)。该位点在多物种之间保守。100个听力正常人未发现此突变。结论 HB-S037家系定位于第11号染色体的长臂11q13.4-14.1之间,致病基因为MYO7A,MYO7A第17外显子c.2011G>A突变引起第671位氨基酸甘氨酸替换为丝氨酸,该突变为HB-S037家系的致病突变,为MYO7A基因的一个新发现的突变位点。

Objective In this study, we identified the causative gene in an autosomal -dominant nonsyndromic hereditary hearing loss Chinese pedigree named HB-S037and studied MYO7A mutation. Methods We mapped the locus on chromosome 11q13.4-q14.1 region using the Affymetrix 5.0 SNP Genechip and linkage analysis. We then refined the mapping and haplotype analysis with 12 microsatellite markers. Finally, we identified the pathogenic gene by direct se- quencing. Results We mapped the locus to a chromosome 11q13.4-q14.1 region （two-point lod-score of 4.346） and we further mapped the same locus to the region between D11S1314 and D11S4166（two-point lod-score of 4.18）. We identi- fied a novel missense mutation c.2011GA（p.G671S） in Exon17 of MYO7A, which was faithfully cosegregated with hear- ing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. Conclusion We mapped the mutation locus in the Chinese pedigree HB-S037 on chromosome 11q13.4-q14.1 region, and identified the pathogenic gene. We confirmed that the novel missense mutation c.2011GA （p.G671S） in Exon17 ofMYO7A was the pathogenic mutation.