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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.

Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation †