Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity.
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.
UCL Ear Institute, University College London, 332 Gray’s Inn Road, London WC1X 8EE, UK. d.jagger@ucl.ac.uk
Daniel
D
Jagger
Gayle
G
Collin
John
J
Kelly
Emily
E
Towers
Graham
G
Nevill
Chantal
C
Longo-Guess
Jennifer
J
Benson
Karin
K
Halsey
David
D
Dolan
Jan
J
Marshall
Jürgen
J
Naggert
Andrew
A
Forge
D056769:Alstrom Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D016764:Cell Polarity; D002502:Centrioles; D002923:Cilia / Q000648:ultrastructure; D003051:Cochlea / Q000648:ultrastructure*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000648:ultrastructure*; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009925:Organ of Corti / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013316:Stria Vascularis / Q000648:ultrastructure
C510001:Alms1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins