International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


ORAL PRESENTATION

MONDAY 10 NOVEMBER
14:30 – 14:45 HRS

A FUNCTIONAL SINGLE NUCLEOTIDE POLYMORPHISM IN CADHERIN 23 IS ASSOCIATED WITH POLYGENIC INHERITANCE AND GENETIC MODIFICATION OF SENSORINEURAL HEARING LOSS IN MICE

Noben-Trauth K
National Institute on Deafness and Other Communication Disorders

Co-Authors: Zheng Q Y, Johnson K R
Institutions: The Jackson Laboratory

Quantitative trait loci (QTL) and genetic modifiers are main determinants of phenotypic variation and disease susceptibility in humans and animal models. Age-related hearing loss (AHL) in mice is a genetically complex trait and parallels pathology and etiology of sensorineural presbycusis in humans. A major QTL for AHL has been mapped to mouse chromosome 10. W used a positional cloning strategy, based on segregation analyses in multiple crosses, to identify a synonymous single nucleotide polymorphism (SNP) in Cdh23 associated with AHL and genetic modification (mdfw). The 753G>A SNP shows significant association (p=2x10-5) with hearing thresholds in 56 inbred strains. The Cdh23753A variant causes in-frame skipping of exon 7, producing a protein with two truncated cadherin-repeats near the amino-terminus. Accumulation of alternatively spliced transcripts precedes onset of AHL. Cdh23753A fails to complement loss of functional CDH23 and is a hypomorphic allele. These observations suggest a polygenic inheritance model for AHL in which a combination of Cdh23753A and other factors (Atp2b2dfw-2J, mt-Tr 9827ins8, or ahl2) is necessary and sufficient for AHL manifestation. Altered adhesion function or reduced stability of CDH23 confers susceptibility to AHL. These data may provide a paradigm for predisposition to age-related and noise-induced hearing loss in humans.


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