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Human Molecular Genetics Advance Access published online on November 10, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi010
© 2004 by Oxford University Press
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Article

Digenic inheritance of deafness caused by mutations in the genes encoding cadherin 23 and protocadherin 15 in mice and humans

Qing Yin Zheng 1, Denise Yan 2, Xiao Mei Ouyang 2, Li Lin Du 2, Heping Yu 1, Bo Chang 1, Kenneth R Johnson 1, and Xue Zhong Liu 3*

1 The Jackson Laboratory, Bar Harbor, ME 04609, USA
2 Department of Otolaryngology, University of Miami, Miami, Florida 33101, USA
3 Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, Florida 33136, USA

* To whom correspondence should be addressed.
Xue Zhong Liu, E-mail: xliu{at}med.miami.edu


  Abstract

Mutations in the 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.


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