Document Detail

Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity.
MedLine Citation:
PMID:  21071598     Owner:  NLM     Status:  MEDLINE    
Alström Syndrome is a life-threatening disease characterized primarily by numerous metabolic abnormalities, retinal degeneration, cardiomyopathy, kidney and liver disease, and sensorineural hearing loss. The cellular localization of the affected protein, ALMS1, has suggested roles in ciliary function and/or ciliogenesis. We have investigated the role of ALMS1 in the cochlea and the pathogenesis of hearing loss in Alström Syndrome. In neonatal rat organ of Corti, ALMS1 was localized to the basal bodies of hair cells and supporting cells. ALMS1 was also evident at the basal bodies of differentiating fibrocytes and marginal cells in the lateral wall. Centriolar ALMS1 expression was retained into maturity. In Alms1-disrupted mice, which recapitulate the neurosensory deficits of human Alström Syndrome, cochleae displayed several cyto-architectural defects including abnormalities in the shape and orientation of hair cell stereociliary bundles. Developing hair cells were ciliated, suggesting that ciliogenesis was largely normal. In adult mice, in addition to bundle abnormalities, there was an accelerated loss of outer hair cells and the progressive appearance of large lesions in stria vascularis. Although the mice progressively lost distortion product otoacoustic emissions, suggesting defects in outer hair cell amplification, their endocochlear potentials were normal, indicating the strial atrophy did not affect its function. These results identify previously unrecognized cochlear histopathologies associated with this ciliopathy that (i) implicate ALMS1 in planar cell polarity signaling and (ii) suggest that the loss of outer hair cells causes the majority of the hearing loss in Alström Syndrome.
Daniel Jagger; Gayle Collin; John Kelly; Emily Towers; Graham Nevill; Chantal Longo-Guess; Jennifer Benson; Karin Halsey; David Dolan; Jan Marshall; Jürgen Naggert; Andrew Forge
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-11
Journal Detail:
Title:  Human molecular genetics     Volume:  20     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-07     Completed Date:  2011-07-19     Revised Date:  2014-11-05    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  466-81     Citation Subset:  IM    
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MeSH Terms
Alstrom Syndrome / genetics,  metabolism*,  pathology*
Cell Differentiation
Cell Polarity
Cilia / ultrastructure
Cochlea / ultrastructure*
DNA-Binding Proteins / genetics,  metabolism*
Fluorescent Antibody Technique
Hair Cells, Auditory / metabolism*,  ultrastructure*
Hearing Loss / genetics*,  metabolism,  pathology*
Mice, Knockout
Microscopy, Electron
Organ of Corti / ultrastructure
Rats, Sprague-Dawley
Signal Transduction
Stria Vascularis / ultrastructure
Grant Support
BB/D009669/1//Biotechnology and Biological Sciences Research Council; DC04301/DC/NIDCD NIH HHS; HD036878/HD/NICHD NIH HHS; P30 DC05188/DC/NIDCD NIH HHS; R01 DC004301/DC/NIDCD NIH HHS; R01 HD036878/HD/NICHD NIH HHS
Reg. No./Substance:
0/Alms1 protein, mouse; 0/DNA-Binding Proteins

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