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.
American Journal of Medical Genetics Part A 06/2011; 155A(6):1298-313. · 2.39 Impact Factor
ABSTRACT: To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss.
Prospective molecular genetic research study.
Academic genetic research laboratory.
Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses.
Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis.
Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation.
Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single-nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34-p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate-binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation.
Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4.
Archives of otolaryngology--head & neck surgery 01/2011; 137(1):54-9. · 1.92 Impact Factor
ABSTRACT: Wolfram syndrome is characterized by optic atrophy, insulin dependent diabetes mellitus, diabetes insipidus and deafness. There are several other associated conditions reported in the literature, but congenital or early childhood cataracts are not among them.
Observational case series with confirmatory genetic analysis.
A pair of siblings, followed over 17 years, who manifest congenital or early childhood cataracts, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. They are both compound heterozygotes for mutations (V415 deletion and A684V substitution) in the WFS1 gene. Their father has congenital sensorineural hearing loss and developed optic atrophy. He is heterozygous for A684V in WFS1.
Wolfram syndrome should be in the differential diagnosis of genetic syndromes associated with congenital and early childhood cataracts. Here, we report on a mother who is a phenotypically normal carrier of an autosomal recessive Wolfram syndrome gene, and a father who has some of the findings of the syndrome and carries a single mutation that appears to be responsible for his hearing loss and optic atrophy. Their 2 children are compound heterozygotes and manifest the full Wolfram syndrome, in addition to cataracts.
Ophthalmic Genetics 12/2010; 31(4):227-9. · 0.93 Impact Factor
ABSTRACT: Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G>A, g. 48G>A mutation in a highly conserved region of the 5' UTR. The c.-172G>A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (approximately 1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G>A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy.
Proceedings of the National Academy of Sciences 07/2010; 107(30):13396-401. · 9.68 Impact Factor