Human Molecular Genetics Advance Access originally published online on May 3, 2009
Human Molecular Genetics 2009 18(15):2748-2760; doi:10.1093/hmg/ddp210
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Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation
,*1 Department of Otolaryngology Head & Neck Surgery 2 Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA 3 Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720-3190, USA 4 Department of Biological Structure, University of Washington, Seattle, WA 98195, USA 5 Department of Communication Sciences and Disorders, East Carolina University, Greenville, NC 27858, USA 6 Department of Otolaryngology Head & Neck Surgery, Southwestern Medical Center, Dallas, TX 75235, USA
* To whom correspondence should be addressed at: 11100 Euclid Ave., CWRU, Cleveland, OH 44106; USA. Tel: +1 2168447261; Fax: +1 2169830284; Email: kna3{at}case.edu
Received March 17, 2009; Accepted April 29, 2009
Usher syndrome 3A (USH3A) is an autosomal recessive disorder characterized by progressive loss of hearing and vision due to mutation in the clarin-1 (CLRN1) gene. Lack of an animal model has hindered our ability to understand the function of CLRN1 and the pathophysiology associated with USH3A. Here we report for the first time a mouse model for ear disease in USH3A. Detailed evaluation of inner ear phenotype in the Clrn1 knockout mouse (Clrn1–/–) coupled with expression pattern of Clrn1 in the inner ear are presented here. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells (OHCs) than inner hair cells. Clrn1–/– mice showed early onset hearing loss that rapidly progressed to severe levels. Two to three weeks after birth (P14–P21), Clrn1–/– mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By P21, 
70% of Clrn1–/– mice had no detectable ABR and by P30 these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1–/– mice. Vestibular function in Clrn1–/– mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of OHC stereocilia was seen as early as P2 and by P21 OHC loss was observed. In sum, hair cell dysfunction and prolonged peak latencies in vestibular and cochlear evoked potentials in Clrn1–/– mice strongly indicate that Clrn1 is necessary for hair cell function and associated neural activation.
This work is dedicated to Cindy Elden. We appreciate the vision, inspiration and generosity of the Elden family that made this work possible.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors and the last two authors should be regarded as joint Senior Authors.
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  G. Tian, Y. Zhou, D. Hajkova, M. Miyagi, A. Dinculescu, W. W. Hauswirth, K. Palczewski, R. Geng, K. N. Alagramam, J. Isosomppi, et al. Clarin-1, Encoded by the Usher Syndrome III Causative Gene, Forms a Membranous Microdomain: POSSIBLE ROLE OF CLARIN-1 IN ORGANIZING THE ACTIN CYTOSKELETON J. Biol. Chem., July 10, 2009; 284(28): 18980 - 18993. [Abstract] [Full Text] [PDF]
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