Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss
Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss
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新型 TRRAP 突变导致常染色体显性非综合征性听力损失
DOI：
10.1111/cge.13590
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发表时间：
2019-07-10
影响因子：
3.5
通讯作者：
Ma, Duan
中科院分区：
文献类型：
--
作者：
Xia, Wenjun;Hu, Jiongjiong;Ma, Duan
遗传性非综合征性听力损失是人类最常见的遗传性感觉缺陷。超过40个基因已被确定为常染色体显性非综合征性听力损失（ADNSHL）的致病基因，但仍有许多其他候选基因有待发现。我们的目的是确定一个中国人的语言后进行性ADNSHL的致病基因突变。采用全外显子组测序、生物信息学分析和桑格测序等方法，验证了一个三代ADNSHL家系中与听力损失相关的转录/转录结构域相关蛋白基因的一个新致病性变异（NM_ 001244580，c.511 C>T，p.Arg171 Cys）的共分离。此外，在66例散发性听力损失病例中检测到三种新的转化/转录结构域相关蛋白（TRRAP）变体。构建吗啉代寡核苷酸敲除和成簇的规则间隔的短回文重复序列/Cas9敲除斑马鱼以验证遗传发现。TRRAP基因的敲除或敲除导致斑马鱼内耳明显缺陷，表明TRRAP在内耳发育中起重要作用。结论：TRRAP（NM_ 001244580，c.511C>T，p.Arg171Cys）基因在一个中国人ADNSHL家系中与听力障碍共分离，TRRAP基因缺失导致斑马鱼听力障碍，提示TRRAP基因可能与ADNSHL相关。
Hereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. More than 40 genes have been identified as causative genes for autosomal dominant non-syndromic hearing loss (ADNSHL), but there are many other candidate genes that remain to be discovered. We aimed to identify the causative gene mutation for post-lingual progressive ADNSHL in a Chinese family. Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant (NM_ 001244580, c.511C>T, p.Arg171Cys) in the TRansformation/tRanscription domain-Associated Protein gene associated with hearing loss in a three-generation Chinese family with ADNSHL). Additionally, three more novel variants of transformation/transcription domain associated protein (TRRAP) were detected in 66 sporadic cases of hearing loss. Morpholino oligonucleotides knockdown and clustered regularly interspaced short palindromic repeats/Cas9 knockout zebrafish were constructed to validate the genetic findings. Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development. In conclusion, TRRAP (NM_ 001244580, c.511C>T, p.Arg171Cys) co-segregated with hearing loss in a Chinese family with ADNSHL, and TRRAP deficiency caused hearing disability in zebrafish, suggesting TRRAP is a gene associated with ADNSHL.