title: Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations.
abstract: Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Cryns
authors.forename: Markus
authors.initials: M
authors.lastname: Pfister
authors.forename: Ronald J E
authors.initials: RJ
authors.lastname: Pennings
authors.forename: Steven J H
authors.initials: SJ
authors.lastname: Bom
authors.forename: Kris
authors.initials: K
authors.lastname: Flothmann
authors.forename: Goele
authors.initials: G
authors.lastname: Caethoven
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schatteman
authors.forename: Karen A
authors.initials: KA
authors.lastname: Köln
authors.forename: Tímea
authors.initials: T
authors.lastname: Tóth
authors.forename: Susan
authors.initials: S
authors.lastname: Kupka
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Blin
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Paul H
authors.initials: PH
authors.lastname: van de Heyning
authors.forename: William
authors.initials: W
authors.lastname: Reardon
authors.forename: Dafydd
authors.initials: D
authors.lastname: Stephens
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D001299:Audiometry; D004252:DNA Mutational Analysis; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D005810:Multigene Family / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein