Mutations in Grxcr1 are the basis for inner ear dysfunction in the pirouette mouse.
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.
Odeh
Hana
H
Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Hunker
Kristina L
KL
Belyantseva
Inna A
IA
Azaiez
Hela
H
Avenarius
Matthew R
MR
Zheng
Lili
L
Peters
Linda M
LM
Gagnon
Leona H
LH
Hagiwara
Nobuko
N
Skynner
Michael J
MJ
Brilliant
Murray H
MH
Allen
Nicholas D
ND
Riazuddin
Saima
S
Johnson
Kenneth R
KR
Raphael
Yehoash
Y
Najmabadi
Hossein
H
Friedman
Thomas B
TB
Bartles
James R
JR
Smith
Richard J H
RJ
Kohrman
David C
DC
D008841:Actin Cytoskeleton; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D007758:Ear, Inner / Q000503:physiopathology*; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics*; D054477:Glutaredoxins / Q000737:chemistry / Q000235:genetics*; D034381:Hearing Loss / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D021381:Protein Transport
D054477:Glutaredoxins; C547811:Grxcr1 protein, mouse