title: Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.
abstract: Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Denmark.
authors.forename: Nanna D
authors.initials: ND
authors.lastname: Rendtorff
authors.forename: Marianne
authors.initials: M
authors.lastname: Lodahl
authors.forename: Houda
authors.initials: H
authors.lastname: Boulahbel
authors.forename: Ida R
authors.initials: IR
authors.lastname: Johansen
authors.forename: Arti
authors.initials: A
authors.lastname: Pandya
authors.forename: Katherine O
authors.initials: KO
authors.lastname: Welch
authors.forename: Virginia W
authors.initials: VW
authors.lastname: Norris
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Arnos
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Emery
authors.forename: Marilyn B
authors.initials: MB
authors.lastname: Mets
authors.forename: Toril
authors.initials: T
authors.lastname: Fagerheim
authors.forename: Kristina
authors.initials: K
authors.lastname: Eriksson
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Helene
authors.initials: H
authors.lastname: Bruhn
authors.forename: Claes
authors.initials: C
authors.lastname: Möller
authors.forename: Sture
authors.initials: S
authors.lastname: Lindholm
authors.forename: Stefan
authors.initials: S
authors.lastname: Ensgaard
authors.forename: Marci M
authors.initials: MM
authors.lastname: Lesperance
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjaerg
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009896:Optic Atrophy / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013548:Sweden; D006113:United Kingdom; D014481:United States; D014929:Wolfram Syndrome / Q000235:genetics*
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; C114987:wolframin protein; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human