Dataset Information

HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.

ABSTRACT: 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.

SUBMITTER: Azaiez H

PROVIDER: S-EPMC4376867 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.

Azaiez Hela H Decker Amanda R AR Booth Kevin T KT Simpson Allen C AC Shearer A Eliot AE Huygen Patrick L M PL Bu Fengxiao F Hildebrand Michael S MS Ranum Paul T PT Shibata Seiji B SB Turner Ann A Zhang Yuzhou Y Kimberling William J WJ Cornell Robert A RA Smith Richard J H RJ

PLoS genetics 20150327 3

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 comp ...[more]

PMID: 25816005

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Project description:Research suggests that college-aged adults are vulnerable to tinnitus and hearing loss due to exposure to traumatic levels of noise on a regular basis. Recent human studies have associated exposure to high noise exposure background (NEB, i.e., routine noise exposure) with the reduced cochlear output and impaired speech processing ability in subjects with clinically normal hearing sensitivity. While the relationship between NEB and the functions of the auditory afferent neurons are studied in the literature, little is known about the effects of NEB on functioning of the auditory efferent system. The objective of the present study was to investigate the relationship between medial olivocochlear reflex (MOCR) strength and NEB in subjects with clinically normal hearing sensitivity. It was hypothesized that subjects with high NEB would exhibit reduced afferent input to the MOCR circuit which would subsequently lead to reduced strength of the MOCR. In normal-hearing listeners, the study examined (1) the association between NEB and baseline click-evoked otoacoustic emissions (CEOAEs) and (2) the association between NEB and MOCR strength. The MOCR was measured using CEOAEs evoked by 60 dB pSPL linear clicks in a contralateral acoustic stimulation (CAS)-off and CAS-on (a broadband noise at 60 dB SPL) condition. Participants with at least 6 dB signal-to-noise ratio (SNR) in the CAS-off and CAS-on conditions were included for analysis. A normalized CEOAE inhibition index was calculated to express MOCR strength in a percentage value. NEB was estimated using a validated questionnaire. The results showed that NEB was not associated with the baseline CEOAE amplitude (r = -0.112, p = 0.586). Contrary to the hypothesis, MOCR strength was positively correlated with NEB (r = 0.557, p = 0.003). NEB remained a significant predictor of MOCR strength (β = 2.98, t(19) = 3.474, p = 0.003) after the unstandardized coefficient was adjusted to control for effects of smoking, sound level tolerance (SLT) and tinnitus. These data provide evidence that MOCR strength is associated with NEB. The functional significance of increased MOCR strength is discussed.

Project description:Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype-phenotype correlations of DFNA68 hearing loss.

Dataset Information

HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.

Publications

HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.

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