Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1

Abstract

Dominantly inherited progressive hearing loss DFNA38 is caused by heterozygosity for a novel mutation in WFS1, the gene for recessively inherited Wolfram syndrome. Wolfram syndrome is defined by juvenile diabetes mellitus and optic atrophy and may include progressive hearing loss and other neurological symptoms. Heterozygotes for other Wolfram syndrome mutations generally have normal hearing. Dominant deafness defined by DFNA38 is more severe than deafness of Wolfram syndrome patients and lacks any syndromic features. In a six-generation kindred from Newfoundland, Canada, WFS1 Ala716Thr (2146 G-->A) was shared by all deaf members of the family and was specific to deaf individuals. The causal relationship between this missense mutation and deafness was supported by two observations based on haplotype and mutation analysis of the kindred. First, a relative homozygous for the mutation was diagnosed at age 3 years with insulin-dependent diabetes mellitus, the central feature of Wolfram syndrome. Second, two relatives with normal hearing had an identical haplotype to that defining DFNA38, with the exception of the base pair at position 2146. Other rare variants of WFS1 co-inherited with deafness in the family could be excluded as disease-causing mutations on the basis of this hearing-associated haplotype. The possibility that 'mild' mutations in WFS1 might be a cause of non-syndromic deafness in the general population should be explored.

Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

“…Table 1 compares the clinical features of these sisters and patients from family 1. Considering the mild clinical features of two other missense mutations in the literature (A716T 24 and P885L 17 ), Van ven Ouweland et al 18 suggested a correlation between the type of the mutation and severity of the disease; homozygosity or compound heterozygosity for missense mutations lead to an attenuated form of the disease, whereas protein-truncating mutations may cause severe WFS. This is in contrast to our findings that describe the same missense mutation associated with severe WFS, defined as neurodegenerative involvement.…”

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

“…11 WFS1 has also been associated with an autosomal dominant form of low-frequency sensorineural hearing loss, [12][13][14] autosomal dominant OA, [14][15][16] type 2 diabetes, [17][18][19] and psychiatric problems. 9,15,20 WFS1 has eight exons; the first one is noncoding and comprises 33.4 kbp on chromosome 4p16.1.…”

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15

“…We have identified three extended multiplex families with neurosensory hearing loss (Figure 1a), two with autosomal recessive prelingual deafness (Families A and B) and one with a rare form of low frequency loss segregating as an autosomal dominant trait (Family C). We previously used a traditional linkage approach to reveal that a missense mutation in the WFS1 gene causes low frequency hearing loss in Family C. 9 As of this report, the WFS1 gene reportedly accounts for the vast majority of cases of low frequency hearing loss worldwide, 13,14 a gene previously associated with a syndromic form of optic atrophy (Wolfram syndrome, OMIM no. 222300).…”