Human Molecular Genetics, 2001, Vol. 10, No. 22 2509-2514
© 2001 Oxford University Press
Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1
Departments of Genomic Sciences and Medicine, University of Washington, Seattle, WA 98195-7720, USA, 1Division of Medical Genetics, Memorial University of Newfoundland, St John’s, NF A1B 3V6, Canada 2Department of Medical Genetics, Alberta Children’s Hospital, Calgary, AB T3E 4R3, Canada, 3Department of Audiology, Health Care Corporation of St John’s, St John’s, NF A1A 1R8, Canada and 4Central Newfoundland Regional Health Center, Grand Falls-Windsor, NF A2A 2E1, Canada
Dominantly inherited progressive hearing loss DFNA38 is caused by heterozygosity for a novel mutation in WFS1, the gene for recessively inherited Wolfram syndrome. Wolfram syndrome is defined by juvenile diabetes mellitus and optic atrophy and may include progressive hearing loss and other neurological symptoms. Heterozygotes for other Wolfram syndrome mutations generally have normal hearing. Dominant deafness defined by DFNA38 is more severe than deafness of Wolfram syndrome patients and lacks any syndromic features. In a six-generation kindred from Newfoundland, Canada, WFS1 Ala716Thr (2146 G
A) was shared by all deaf members of the family and was specific to deaf individuals. The causal relationship between this missense mutation and deafness was supported by two observations based on haplotype and mutation analysis of the kindred. First, a relative homozygous for the mutation was diagnosed at age 3 years with insulin-dependent diabetes mellitus, the central feature of Wolfram syndrome. Second, two relatives with normal hearing had an identical haplotype to that defining DFNA38, with the exception of the base pair at position 2146. Other rare variants of WFS1 co-inherited with deafness in the family could be excluded as disease-causing mutations on the basis of this hearing-associated haplotype. The possibility that ‘mild’ mutations in WFS1 might be a cause of non-syndromic deafness in the general population should be explored.
+ To whom correspondence should be addressed. Tel: +1 206 616 4297; Fax: +1 206 616 4295; Email: tlyoung@u.washington.edu
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