Progressive hearing loss and increased susceptibility to noise-induced hearing loss in mice carrying a Cdh23 but not a Myo7a mutation.

Exposure to intense noise can damage the stereocilia of sensory hair cells in the inner ear. Since stereocilia play a vital role in the transduction of sound from a mechanical stimulus into an electrical one, this pathology is thought to contribute to noise-induced hearing loss. Mice homozygous for null mutations in either the myosin VIIa ( Myo7a) or cadherin 23 ( Cdh23) genes are deaf and have disorganized stereocilia bundles.

Cdh23 mutations in the mouse are associated with retinal dysfunction but not retinal degeneration.

Mutations in the cadherin 23 gene (CDH23) cause Usher syndrome type 1D in humans, a disease that results in retinitis pigmentosa and deafness. Cdh23 is also mutated in the waltzer mouse. In order to determine if the retina of the waltzer mouse undergoes retinal degeneration and to gain insight into the function of cadherin 23 in the retina, we have characterized the anatomy and physiology of retinas of waltzer mouse mutants.

Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31.

The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31.

Elongation of hair cell stereocilia is defective in the mouse mutant whirler.

The recessive mouse mutant whirler (wi) shows no response to sound and exhibits circling and head-tossing behaviour, indicative of both auditory and vestibular dysfunction. The wi mutation maps genetically to mouse chromosome 4. We examined the organ of Corti of whirler mutants to explore the possibility that the wi mutation affects sensory hair cells.

Stereocilia defects in waltzer (Cdh23), shaker1 (Myo7a) and double waltzer/shaker1 mutant mice.

Mutations in myosin VIIa (Myo7a) and cadherin 23 (Cdh23) cause deafness in shaker1 (sh1) and waltzer (v) mouse mutants respectively. In humans, mutations in these genes cause Usher's syndrome type 1B and D respectively, as well as certain forms of non-syndromic deafness. Examination of the organ of Corti from shaker1 and waltzer mice has shown that these genes are required for the proper organisation of hair cell stereocilia.