IDENTIFICATION OF A GENE INVOLVED WITH STEREOCILIA ELONGATION : POSITIONAL CLONING OF THE MOUSE wi DEAFNESS LOCUS
MRC Mammmalian Genetics Unit & Mouse Genome Centre
OXON OX11 0RD UK
Co-Authors: Varela-Carver A.,Holme RH, Hardisty RE, White D, Paige A, Fleming J, Rogers M, Kiernan BW, Steel KP, Brown SDM
Institutions: MRC Mammalian Genetics Unit and Mouse Genome Centre, MRC Institute of Hearing Research
Genetic deafness is highly prevalent in the human population, affecting 1 in 2000 births. Many of these show primary abnormalities of the sensory epithelia of the inner ear, as do several mouse mutants. In the whirler (wi) mutant the stereocilia of the inner hair cells of the cochlear duct are considerably shorter than wild-type while outer hair cell stereocilia take on a more rounded U shape compared to the normal V or W shape. Cloning of the defective gene underlying wi will provide insight into the molecular processes involved in normal development of stereocilia as well as providing valuable insights into the causes of neuroepithelial deafness.
The wi non-recombinant region is contained within a minimal tiling path consisting of 2 BACs and a PAC. One of the BACs has been used in transgenic rescue experiments and been shown to rescue the inner hair cell phenotype of wi mutant mice, while there is partial rescue of the outer hair cell phenotype. Whirler mice carrying the BAC also demonstrate a normal Preyer reflex up to P95 and an absence of the usual circling and head tossing behaviour normally associated with the wi mutant. One of the genes in the BAC carries a mutation in wi mice and is expressed from the BAC in the rescued mutant mice. The gene encodes a PDZ protein and represents a provocative novel candidatemolecule involved in steriocilia development.