Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness
Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness
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DOI：
10.1111/cge.13422
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发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Liu, Y.
中科院分区：
文献类型：
--
作者：
Lu, X.;Wang, Q.;Liu, Y.
听力损失是世界上最常见的感觉障碍之一，其中约一半可归因于遗传因素。在这里，我们在一个常染色体显性、非综合征性听力损失的中国家庭中发现了一种新的HOMER2致病变异。这是全球报告的第二个由HOMER2变异引起听力损失的家庭。HOMER2 （NM_199330）的致病性变异c.840_841insC与家族中听力损失表型分离，导致过早停止密码子产生截断蛋白。HOMER2蛋白c末端的螺旋结构域是蛋白多聚和HOMER2- cdc42相互作用的关键。我们比较了两个家族的表型，发现这个中国家族的听力障碍更严重。此外，我们发现这种插入突变型HOMER2（HOMER2(MU)）的多倍化能力比野生型HOMER2（HOMER2(WT)）和报道的C . 554g >C （NM_004839）突变型HOMER2下降得更明显。HOMER2（MU）蛋白倾向于以弥散方式分布，而HOMER2（WT）和报道的突变体HOMER2倾向于聚集在一起。我们的研究为导致非综合征性感音神经性听力损失的HOMER2变异提供了第二个验证家族。HOMER2的同/异多聚化可能是发挥其正常功能的第一步。
Hearing loss is one of the most common sensory disorders worldwide, and about half of all occurrences are attributable to genetic factors. Here, we have identified a novel pathogenic variant in HOMER2 in a Chinese family with autosomal dominant, non-syndromic hearing loss. This is the second family reported globally with hearing loss caused by a variant in HOMER2. The pathogenic variant c.840_841insC in HOMER2 (NM_199330), segregating with the hearing-loss phenotype in the family, leads to a premature stop codon producing a truncated protein. The coiled-coil domain in the C-terminal of HOMER2 protein is essential for protein multimerization and HOMER2-CDC42 interaction. We compared the phenotypes in the two families and found that hearing impairment in this Chinese family was more severe. Furthermore, we found that the ability of this insertion mutant type HOMER2 (HOMER2(MU)) to multimerize decreased more significantly than wild-type HOMER2 (HOMER2(WT)) and the reported c.554G>C (NM_004839) mutant HOMER2. HOMER2(MU) protein tended to be distributed in a diffuse manner, whereas HOMER2(WT) and the reported mutant HOMER2 tended to cluster together. Our research provides a validating second family for variants in HOMER2 causing non-syndromic sensorineural hearing loss. HOMER2 homo-/hetero-multimerization might be the first step in exerting its normal function.