Azaiez Hela, Decker Amanda R, Booth Kevin T, Simpson Allen C, Shearer A Eliot, Huygen Patrick L M, Bu Fengxiao, Hildebrand Michael S, Ranum Paul T, Shibata Seiji B, Turner Ann, Zhang Yuzhou, Kimberling William J, Cornell Robert A, Smith Richard J H
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
PLoS Genet. 2015 Mar 27;11(3):e1005137. doi: 10.1371/journal.pgen.1005137. eCollection 2015 Mar.
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临床和遗传异质性疾病。迄今为止，已有80多个基因被牵涉其中，随着靶向基因组富集和大规模平行测序（TGE+MPS）的出现，新型耳聋基因的鉴定速度加快。在此，我们报告一个家族，其患有语言后发性进行性常染色体显性非综合征性听力损失（ADNSHL）。在首先使用TGE+MPS排除已知致聋基因中似是而非的变异后，我们对三名听力受损的家族成员进行了全外显子组测序。在这个大家庭中，只有一个变异，即HOMER2基因中的p.Arg185Pro，与听力损失表型共分离。这种氨基酸变化改变了HOMER2卷曲螺旋结构域中一个高度保守的残基，该残基对于蛋白质多聚化和HOMER2与CDC42的相互作用至关重要。作为一种支架蛋白，HOMER2参与细胞内钙稳态和细胞骨架组织。与此功能一致，我们在小鼠内耳毛细胞的静纤毛中发现了强烈表达，并观察到突变型p.Pro185 HOMER2 mRNA的过表达导致斑马鱼胚胎内耳和神经丘的解剖学变化。此外，Homer2靶向缺失的纯合小鼠突变体表现出早发性快速进行性听力损失。这些数据提供了令人信服的证据，表明HOMER2是正常听力所必需的，其在人类中的序列改变通过显性负性作用模式导致ADNSHL。
