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

Hela Azaiez; Amanda R Decker; Kevin T Booth; Allen C Simpson; A Eliot Shearer; Patrick L M Huygen; Fengxiao Bu; Michael S Hildebrand; Paul T Ranum; Seiji B Shibata; Ann Turner; Yuzhou Zhang; William J Kimberling; Robert A Cornell; Richard J H Smith

doi:10.1371/journal.pgen.1005137

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

Journal article

Open access

Peer reviewed

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

Hela Azaiez, Amanda R Decker, Kevin T Booth, Allen C Simpson, A Eliot Shearer, Patrick L M Huygen, Fengxiao Bu, Michael S Hildebrand, Paul T Ranum, Seiji B Shibata, …

PLoS genetics, Vol.11(3), pp.e1005137-e1005137

03/2015

DOI: 10.1371/journal.pgen.1005137

PMCID: PMC4376867

PMID: 25816005

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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.

Stereocilia - pathology

Carrier Proteins - biosynthesis

Humans

RNA, Messenger - genetics

Gene Expression Regulation

Hearing Loss, Sensorineural - pathology

Zebrafish

cdc42 GTP-Binding Protein - metabolism

Hearing Loss, Sensorineural - genetics

Ear, Inner - pathology

Carrier Proteins - genetics

RNA, Messenger - biosynthesis

Ear, Inner - metabolism

Exome - genetics

Stereocilia - genetics

Animals

Cochlea - metabolism

cdc42 GTP-Binding Protein - genetics

Cochlea - pathology

Homer Scaffolding Proteins

High-Throughput Nucleotide Sequencing

Mice

Details

Title: Subtitle: HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice
Creators: Hela Azaiez - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Amanda R Decker - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Kevin T Booth - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Allen C Simpson - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
A Eliot Shearer - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Patrick L M Huygen - Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
Fengxiao Bu - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Michael S Hildebrand - Austin Health, Department of Medicine, University of Melbourne, Melbourne, Australia
Paul T Ranum - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Seiji B Shibata - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Ann Turner - Self-employed physician, Menlo Park, California, United States of America
Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
William J Kimberling - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America
Robert A Cornell - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Richard J H Smith - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.11(3), pp.e1005137-e1005137
DOI: 10.1371/journal.pgen.1005137
PMID: 25816005
PMCID: PMC4376867
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: Public Library Science; United States
Grant note: R01 DC003544 / NIDCD NIH HHS\nR01 DC012049 / NIDCD NIH HHS\nT32 GM007337 / NIGMS NIH HHS\nDC012049 / NIDCD NIH HHS\nR01/ DE021071 / NIDCR NIH HHS\nR01/ AR062547 / NIAMS NIH HHS\nR01S DC003544 / NIDCD NIH HHS
Language: English
Date published: 03/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Psychiatry; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Dental Research; Otolaryngology; Internal Medicine
Record Identifier: 9984007161002771

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