HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.
HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.
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DOI：
10.1371/journal.pgen.1005137
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发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Smith RJ
中科院分区：
文献类型：
--
作者：
Azaiez H;Decker AR;Booth KT;Simpson AC;Shearer AE;Huygen PL;Bu F;Hildebrand MS;Ranum PT;Shibata SB;Turner A;Zhang Y;Kimberling WJ;Cornell RA;Smith RJ
遗传性听力损失是一种临床和遗传异质性疾病。到目前为止，已经有80多个基因被发现，随着靶向基因组富集和大规模并行测序（TGE+MPS）的出现，新的遗传基因鉴定的速度加快了。在这里，我们报告了一个分离的语言后进行性常染色体显性非综合征性听力损失（ADNSHL）的家庭。在首先使用TGE+MPS排除已知的致聋基因中的合理变异后，我们在三个听力受损的家庭成员中完成了全外显子组测序。只有一个单一的变异，p.Arg185Pro在HOMER 2，分离与听力损失表型的大家庭。这种氨基酸变化改变了HOMER 2卷曲螺旋结构域中高度保守的残基，该残基对于蛋白质多聚化和HOMER 2-CDC 42相互作用至关重要。作为一种支架蛋白，HOMER 2参与细胞内钙稳态和细胞骨架组织。与此功能相一致，我们发现在小鼠内耳毛细胞的静纤毛中有强大的表达，并观察到突变型p.Pro185 HOMER 2 mRNA的过度表达会导致斑马鱼胚胎内耳和神经乳突的解剖学变化。此外，Homer 2靶向缺失纯合的小鼠突变体存在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HOMER 2是正常听力所必需的，并且其在人类中的序列改变通过显性负作用模式导致ADNSHL。全世界最常见的感觉障碍是听力障碍。它影响了世界人口的5%以上（3.6亿人），其特征是极端的遗传异质性。超过80个基因与孤立性（也称为“非综合征性”）听力损失有关，并且大量证据支持存在更多“导致听力损失”的基因。在这项研究中，我们使用了序贯筛选策略，首先排除一个分离常染色体显性遗传非综合征性听力损失家族中已知致病基因的因果突变。我们接下来转向全外显子组测序，并确定了一个单一的变异-p. Arg 185 Pro在HOMER 2-与表型分离的大家族。为了验证这种突变的病理意义，我们研究了两种动物模型。在斑马鱼中，我们过表达突变HOMER 2并观察到内耳缺陷;在小鼠中，我们记录了耳蜗毛细胞静纤毛的稳健表达，并证明其缺失会导致早发性进行性耳聋。我们的数据提供了对正常听觉功能和耳蜗毛细胞维持至关重要的基因通路的新见解。
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. The most frequent sensory disorder worldwide is hearing impairment. It impacts over 5% of the world population (360 million persons), and is characterized by extreme genetic heterogeneity. Over 80 genes have been implicated in isolated (also referred to as ‘non-syndromic’) hearing loss, and abundant evidence supports the existence of many more ‘deafness-causing’ genes. In this study, we used a sequential screening strategy to first exclude causal mutations in known deafness-causing genes in a family segregating autosomal dominant non-syndromic hearing loss. We next turned to whole exome sequencing and identified a single variant—p.Arg185Pro in HOMER2—that segregated with the phenotype in the extended family. To validate the pathological significance of this mutation, we studied two animal models. In zebrafish, we overexpressed mutant HOMER2 and observed inner ear defects; and in mice we documented robust expression in stereocilia of cochlear hair cells and demonstrated that its absence causes early-onset progressive deafness. Our data offer novel insights into gene pathways essential for normal auditory function and the maintenance of cochlear hair cells.
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影响因子：
4.5
作者：
Hertzano R;Elkon R;Kurima K;Morrisson A;Chan SL;Sallin M;Biedlingmaier A;Darling DS;Griffith AJ;Eisenman DJ;Strome SE
通讯作者：
Strome SE
影响因子：
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作者：
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通讯作者：
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影响因子：
2.4
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Fagni, L
影响因子：
2.5
作者：
Shiraishi, Y;Mizutani, A;Furuichi, T
通讯作者：
Furuichi, T