Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment
- 28 April 2011
- journal article
- case report
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 155 (6), 1298-1313
- https://doi.org/10.1002/ajmg.a.33970
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.Keywords
This publication has 30 references indexed in Scilit:
- Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS12010
- The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 geneAmerican Journal of Ophthalmology, 2003
- Mutational spectrum of theWFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric diseaseHuman Mutation, 2003
- Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene productHuman Molecular Genetics, 2003
- Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probandsGenetics in Medicine, 2003
- A novel mutation in the OPA1 gene in a Japanese patient with optic atrophyAmerican Journal of Ophthalmology, 2003
- Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing lossHuman Molecular Genetics, 2001
- Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1Human Molecular Genetics, 2001
- Presence of a Major WFS1 Mutation in Spanish Wolfram Syndrome PedigreesMolecular Genetics and Metabolism, 2001
- Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndromeThe Lancet, 1995