» Articles » PMID: 21538838

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.

Citing Articles

The Heterozygous p.A684V Variant in the Gene Is a Mutational Hotspot Causing a Severe Hearing Loss Phenotype.

Otsuka S, Morimoto C, Nishio S, Morita S, Kikuchi D, Takahashi M Genes (Basel). 2025; 16(1).

PMID: 39858604 PMC: 11764508. DOI: 10.3390/genes16010057.


Patients with a Wide Range of Disorders Related to Gene Variants: Novel Mutations and Genotype-Phenotype Correlations.

Grzybowska-Adamowicz J, Gadzalska K, Jakiel P, Juscinska E, Gorzadek M, Skoczylas S Genes (Basel). 2025; 15(12.

PMID: 39766859 PMC: 11675401. DOI: 10.3390/genes15121592.


SID/SIEDP expert consensus on optimizing clinical strategies for early detection and management of wolfram syndrome.

Frontino G, Delvecchio M, Prudente S, Sordi V, Barboni P, Di Giamberardino A J Endocrinol Invest. 2024; 48(3):507-525.

PMID: 39527371 PMC: 11876246. DOI: 10.1007/s40618-024-02495-z.


Wolfram Syndrome 1: A Neuropsychiatric Perspective on a Rare Disease.

Caruso V, Raia A, Rigoli L Genes (Basel). 2024; 15(8).

PMID: 39202345 PMC: 11353439. DOI: 10.3390/genes15080984.


Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of .

Jung J, Jang S, Won D, Gee H, Choi J, Jung J J Clin Med. 2024; 13(16).

PMID: 39200993 PMC: 11355604. DOI: 10.3390/jcm13164851.


References
1.
Mets R, Emery S, Lesperance M, Mets M . Congenital cataracts in two siblings with Wolfram syndrome. Ophthalmic Genet. 2010; 31(4):227-9. DOI: 10.3109/13816810.2010.516056. View

2.
Hofmann S, Philbrook C, Gerbitz K, Bauer M . Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003; 12(16):2003-12. DOI: 10.1093/hmg/ddg214. View

3.
Tessa A, Carbone I, Matteoli M, Bruno C, Patrono C, Patera I . Identification of novel WFS1 mutations in Italian children with Wolfram syndrome. Hum Mutat. 2001; 17(4):348-9. DOI: 10.1002/humu.32. View

4.
Young T, Ives E, Lynch E, Person R, Snook S, Maclaren L . Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet. 2001; 10(22):2509-14. DOI: 10.1093/hmg/10.22.2509. View

5.
Zatyka M, Ricketts C, da Silva Xavier G, Minton J, Fenton S, Hofmann-Thiel S . Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress. Hum Mol Genet. 2007; 17(2):190-200. PMC: 6101208. DOI: 10.1093/hmg/ddm296. View