HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice

Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.遗传性听力损失是一种兼具临床与遗传异质性的疾病。截至目前，已有超过80个基因被证实与该病相关；随着靶向基因组富集与大规模平行测序（TGE+MPS）技术的问世，新发耳聋基因的鉴定速度大幅加快。本研究报道了一个携带有言语后进展性常染色体显性非综合征型听力损失（ADNSHL）的家系。研究人员首先通过TGE+MPS排查了已知致聋基因中的可疑变异，随后对3名听力受损的家系成员开展了全外显子组测序。在该大家系中，仅HOMER2基因的p.Arg185Pro变异与听力损失表型共分离。该氨基酸替换改变了HOMER2卷曲螺旋结构域中一个高度保守的残基，该结构域对于蛋白质多聚化以及HOMER2与CDC42的相互作用至关重要。作为一种脚手架蛋白，HOMER2参与细胞内钙稳态的维持与细胞骨架的构建。与该功能一致，研究人员在小鼠内耳毛细胞的静纤毛中检测到了HOMER2的高表达；同时观察到，突变型p.Pro185 HOMER2 mRNA的过表达会导致斑马鱼胚胎内耳与神经丘的解剖结构异常。此外，携带Homer2靶向纯合敲除的小鼠模型表现出早发性快速进展性听力损失。上述研究结果提供了强有力的证据，证实HOMER2是维持正常听力所必需的，人类中该基因的序列变异通过显性负效应机制可导致ADNSHL。