Human Molecular Genetics Advance Access originally published online on November 10, 2004
Human Molecular Genetics 2005 14(1):103-111; doi:10.1093/hmg/ddi010
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved
Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans
1The Jackson Laboratory, Bar Harbor, ME 04609, USA and 2Department of Otolaryngology, University of Miami, Miami, FL 33101, USA
* To whom correspondence should be addressed at: Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, FL 33136, USA. Tel: +1 3052435695; Fax: +1 3052434925; Email: xliu{at}med.miami.edu
Received September 1, 2004; Accepted October 25, 2004
Mutations in genes coding for cadherin 23 and protocadherin 15 cause deafness in both mice and humans. Here, we provide evidence that mutations at these two cadherin loci can interact to cause hearing loss in digenic heterozygotes of both species. Using a classical genetic approach, we generated mice that were heterozygous for both Cdh23 and Pcdh15 mutations on a uniform C57BL/6J background. Significant levels of hearing loss were detected in these mice when compared to age-matched single heterozygous animals or normal controls. Cytoarchitectural defects in the cochlea of digenic heterozygotes, including degeneration of the stereocilia and a base-apex loss of hair cells and spiral ganglion cells, were consistent with the observed age-related hearing loss of these mice beginning with the high frequencies. In humans, we also have obtained evidence for a digenic inheritance of a USH1 phenotype in three unrelated families with mutations in CDH23 and PCDH15. Altogether, our data indicate that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
AF312024, AF308930, NM033056 and AF281899.
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