外显子组测序一个常染色体显性遗传非综合征型聋家系致病基因ACTG1

摘要

Objective To analyze the clinical audiological characters and to identify the causative gene of a Chinese family with nonsyndromic autosomal dominant inherited hearing loss. Methods Clinical audiological characteristics and inheri-tance pattern of this family were evaluated,and pedigree was drawn based on medical history investigation. Whole exome se-quencing was conducted using DNA samples of two affected members of this family. Candidate mutation was confirmed by Sanger sequencing. Results This Chinese family was characterized by late onset progressive nonsydromic sensorineural hear-ing impairment. Whole exome sequencing revealed a heterozygous missense mutation c.364A>G in exon 4 of ACTG1, causing amino acid substitution Ile to Val at a conservative position 122. The p.I122V substitution is consistent with hearing loss in this Chinese family confirmed by Sanger sequencing. The alteration of conservative residue Ile122 was predicted to damage its interaction with actin-binding proteins, which may cause disruption of hair cell organization and function. Conclusion We have identified and confirmed that the I122V mutation in ACTG1 may have caused autosomal dominant non-syndromic hear-ing impairment in a Chinese family.%目的分析一个遗传性非综合征型耳聋家系的临床听力学特征，应用全外显子组测序技术鉴定该家系的致聋基因。方法通过家系调查，对一个感音神经性聋家系进行临床资料的收集、整理及临床听力学和遗传学特征分析，对家系成员进行调查并绘制系谱图。对2名患病的家系成员进行全外显子组测序确定候选基因，对所有家系成员进行候选基因突变的Sanger测序验证。结果该耳聋家系遗传方式为常染色体显性遗传，患者表现为迟发性、渐进性、早期以高频下降为主的听力损失，全外显子组测序提示已知耳聋基因ACTG1第4外显子存在c.364A>G杂合突变，并引起编码蛋白p.I122V的改变，该位点在多物种之间保守，Sanger测序确认该位点突变与此家系耳聋表型共分离。ACTG1编码的γ-肌动蛋白I122位点的改变可能破坏肌动蛋白纤维的组装，从而影响内耳毛细胞的静纤毛结构和功能。结论该耳聋家系为常染色体显性遗传方式，已知耳聋基因ACTG1第4外显子c.364A>G（p.I122V）突变为该耳聋家系的致病原因。