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December 2011: New Paper on Usher from NIDCD

Background Recessive mutant alleles of MYO7A,USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth.

Methods and results To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele.

Conclusions One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in
deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has
implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome.

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