Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse

Hana Odeh; Kristina L Hunker; Inna A Belyantseva; Hela Azaiez; Matthew R Avenarius; Lili Zheng; Linda M Peters; Leona H Gagnon; Nobuko Hagiwara; Michael J Skynner; Murray H Brilliant; Nicholas D Allen; Saima Riazuddin; Kenneth R Johnson; Yehoash Raphael; Hossein Najmabadi; Thomas B Friedman; James R Bartles; Richard J.H Smith; David C Kohrman

doi:10.1016/j.ajhg.2010.01.016

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Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse

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Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse

Hana Odeh, Kristina L Hunker, Inna A Belyantseva, Hela Azaiez, Matthew R Avenarius, Lili Zheng, Linda M Peters, Leona H Gagnon, Nobuko Hagiwara, Michael J Skynner, …

American journal of human genetics, Vol.86(2), pp.148-160

02/12/2010

DOI: 10.1016/j.ajhg.2010.01.016

PMCID: PMC2820167

PMID: 20137774

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Abstract

Recessive mutations at the mouse pirouette (pi) locus result in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified mutations in the gene Grxcr1 (glutaredoxin cysteine-rich 1) in five independent allelic strains of pirouette mice. We also provide sequence data of GRXCR1 from humans with profound hearing loss suggesting that pirouette is a model for studying the mechanism of nonsyndromic deafness DFNB25. Grxcr1 encodes a 290 amino acid protein that contains a region of similarity to glutaredoxin proteins and a cysteine-rich region at its C terminus. Grxcr1 is expressed in sensory epithelia of the inner ear, and its encoded protein is localized along the length of stereocilia, the actin-filament-rich mechanosensory structures at the apical surface of auditory and vestibular hair cells. The precise architecture of hair cell stereocilia is essential for normal hearing. Loss of function of Grxcr1 in homozygous pirouette mice results in abnormally thin and slightly shortened stereocilia. When overexpressed in transfected cells, GRXCR1 localizes along the length of actin-filament-rich structures at the dorsal-apical surface and induces structures with greater actin filament content and/or increased lengths in a subset of cells. Our results suggest that deafness in pirouette mutants is associated with loss of GRXCR1 function in modulating actin cytoskeletal architecture in the developing stereocilia of sensory hair cells.

Details

Title: Subtitle: Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse
Creators: Hana Odeh - Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Kristina L Hunker - Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Inna A Belyantseva - Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA
Hela Azaiez - Department of Otolaryngology and the Interdepartmental Ph.D. Genetic Program, The University of Iowa, Iowa City, Iowa 52242, USA
Matthew R Avenarius - Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Lili Zheng - Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Linda M Peters - Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA
Leona H Gagnon - The Jackson Laboratory, Bar Harbor, Maine 04609, USA
Nobuko Hagiwara - Department of Pediatrics, The University of Arizona College of Medicine, Steele Memorial Children's Research Center, Tucson, AZ 85724, USA
Michael J Skynner - Neurobiology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK
Murray H Brilliant - Department of Pediatrics, The University of Arizona College of Medicine, Steele Memorial Children's Research Center, Tucson, AZ 85724, USA
Nicholas D Allen - Neurobiology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK
Saima Riazuddin - Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA
Kenneth R Johnson - The Jackson Laboratory, Bar Harbor, Maine 04609, USA
Yehoash Raphael - Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Hossein Najmabadi - Genetic Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Thomas B Friedman - Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA
James R Bartles - Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Richard J.H Smith - Department of Otolaryngology and the Interdepartmental Ph.D. Genetic Program, The University of Iowa, Iowa City, Iowa 52242, USA
David C Kohrman - Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.86(2), pp.148-160
DOI: 10.1016/j.ajhg.2010.01.016
PMID: 20137774
PMCID: PMC2820167
NLM abbreviation: Am J Hum Genet
ISSN: 0002-9297
eISSN: 1537-6605
Publisher: Elsevier Inc
Language: English
Date published: 02/12/2010
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006301602771

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