International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


PLENARY PRESENTATION

TUESDAY 11 NOVEMBER
09:00 – 09:30 HRS

MOUSE MODELS FOR USHER SYNDROME

Karen Steel
The Wellcome Trust Sanger Institute and MRC Institute of Hearing Research

Co-Authors: 2) R Libby, 2) R Holme, 2) T Self, 3) W Marcotti, 4) D Williams and 3) C Kros
Institutions: 2) MRC Institute of Hearing Research, 3) School of Biological Sciences,

4) Department of Neurosciences, UCSD School of Medicine.

People with the most severe form of Usher syndrome have deafness and balance problems from birth, and develop progressive retinitis pigmentosa during the first decade of life. At least eleven genes can be involved in Usher syndrome, and several of these have been identified following discovery of the mouse orthologue. We have examined mice with mutations in two of these genes, Myo7a and Cdh23. Both show primary defects of the stereocilia bundle projecting from the top of sensory hair cells in the inner ear. This bundle normally forms a neat V-shaped array on cochlear hair cells, but in the mutants, the array becomes progressively more disorganised during development. Electrophysiological recordings from single Myo7a mutant hair cells together with the known localisation of Myo7a protein just below the cell membrane covering the stereocilia suggest that Myo7a serves to anchor the cell membrane to the actin core, and loss of this anchoring function affects the mechanical opening of the transduction channel located in stereocilia membranes as well as cohesion of the bundle into its normal array. In the eye, electroretinography reveals reduced a- and b-wave amplitudes in some mutant alleles of Myo7a and Cdh23, and these mutants are also relatively resistant to light-induced retinal damage, suggesting that Myo7a and Cdh23 molecules are involved in photoreceptor cell activation. These findings provide clues to the underlying pathological processes in humans with MYO7A and CDH23 mutations.


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