title: Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1.
abstract: 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.
authors.affiliation: Department of Genomic Sciences, University of Washington, Seattle, WA 98195-7720, USA. tlyoung@u.washington.edu
authors.forename: T L
authors.initials: TL
authors.lastname: Young
authors.forename: E
authors.initials: E
authors.lastname: Ives
authors.forename: E
authors.initials: E
authors.lastname: Lynch
authors.forename: R
authors.initials: R
authors.lastname: Person
authors.forename: S
authors.initials: S
authors.lastname: Snook
authors.forename: L
authors.initials: L
authors.lastname: MacLaren
authors.forename: T
authors.initials: T
authors.lastname: Cater
authors.forename: A
authors.initials: A
authors.lastname: Griffin
authors.forename: B
authors.initials: B
authors.lastname: Fernandez
authors.forename: M K
authors.initials: MK
authors.lastname: Lee
authors.forename: M C
authors.initials: MC
authors.lastname: King
authors.forename: T
authors.initials: T
authors.lastname: Cator
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005192:Family Health; D005260:Female; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D026801:Synteny; D014929:Wolfram Syndrome / Q000235:genetics / Q000473:pathology
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein; D004247:DNA