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Novel loss-of-function mutations in COCH cause autosomal recessive nonsyndromic hearing loss.
Human Genetics ( IF 3.8 ) Pub Date : 2020-06-19 , DOI: 10.1007/s00439-020-02197-5
Kevin T Booth 1, 2 , Amama Ghaffar 3 , Muhammad Rashid 4 , Luke T Hovey 1 , Mureed Hussain 3 , Kathy Frees 1 , Erika M Renkes 1 , Carla J Nishimura 1 , Mohsin Shahzad 5 , Richard J Smith 1 , Zubair Ahmed 3 , Hela Azaiez 1 , Saima Riazuddin 3
Affiliation  

COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.



中文翻译:

COCH中新的功能丧失突变导致常染色体隐性隐性非综合征性听力丧失。

COCH是耳蜗中表达最丰富的基因。毫不奇怪,COCH突变会在小鼠和人类中造成听力损失。两种形式的听力损失与COCH的突变有关,一种是公认的常染色体显性非综合征性听力损失,具有或不具有前庭功能障碍(DFNA9),是通过功能获得/显性阴性机制,最近是常染色体隐性非综合征性听力废话变体造成的损失(DFNB110)。通过结合靶向基因组,外显子组测序和功能研究,我们在COCH中鉴定出四个新的致病变异(两个无意义变异,一个错义和一个读框缺失)在多族裔人群中是常染色体隐性遗传性听力下降的原因。为了研究非截短变体是否通过功能丧失机制发挥作用,我们使用了小基因剪接测定法。我们的数据显示,通过创建外显子剪接沉默子和废除外显子剪接增强子,错义和框内缺失变体均改变了RNA剪接。两种变体均产生移码,并预测将导致无效等位基因。这项研究证实了常染色体隐性非综合征性听力丧失中COCH功能丧失突变的参与,扩大了DFNB110的突变范围,使其包括改变RNA剪接的编码变体,并强调需要研究编码变体对RNA剪接的影响。

更新日期:2020-06-19
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