Dataset Information

Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1.

ABSTRACT:

Purpose

To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series.

Methods

Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members.

Results

All affected individuals showed loss of neuroretinal rim of the optic nerve at fundoscopy with enlarged blind spots at perimetry. They showed a red-green color vision defect at color vision tests and deviations at visually evoked response tests. The audiograms of the affected individuals showed hearing loss and were relatively flat. The unaffected individuals showed no visual deviations or hearing impairment. The affected family members had no glucose intolerance. Leber hereditary optic neuropathy (LHON) mitochondrial mutations and mutations in the Optic atrophy-1 gene (OPA1) were excluded. In the affected individuals, a novel missense mutation c.2508G>C (p.Lys836Asn) in exon 8 of WFS1 was identified.

Conclusions

This study describes the phenotype of a family with autosomal dominant optic neuropathy and hearing impairment associated with a novel missense mutation in WFS1.

SUBMITTER: Hogewind BF

PROVIDER: S-EPMC2805421 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Publications

Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1.

Hogewind Barend F T BF Pennings Ronald J E RJ Hol Frans A FA Kunst Henricus P M HP Hoefsloot Elisabeth H EH Cruysberg Johannes R M JR Cremers Cor W R J CW

Molecular vision 20100112

<h4>Purpose</h4>To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series.<h4>Methods</h4>Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members.<h4>Results</h4>All affected individuals showed loss of neuroretinal rim of the optic ...[more]

PMID: 20069065

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Project description:Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

Dataset Information

Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1.

Purpose

Methods

Results

Conclusions

Publications

Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1.

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