Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss

Abstract

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.

Figure 1.

Pure tone audiogram of 24-year-old female (111:7) from Family 59 with LFSNHL typical of DFNA6/14 phenotype. Circles, air conduction right ear; crosses, air conduction left ear. Masked bone conduction curves follow air conduction curves (not shown).

Figure 2.

Haplotype analysis of key individuals in Family 59 for markers on 4pl6 (telomeric to centromeric). Shaded symbols indicate those affected with LFSNHL. Open symbols indicate normal hearing. Bars indicate haplotypes with solid black bars denoting haplotype shared by affected family members. Solid black line in haplotype indicates indeterminate phase. Centromeric boundary is defined by a recombination event between D4S827 and D4S431 (II:1,II:3,III:1). The telomeric boundary is defined by a recombination event between D4S2354 and D4S827 (III:7). III:4 is shaded consistent with her affection status prior to linkage analysis, but III:4 does not share the haplotype common to the other affected individuals at D4S432 and below. Note that III:4 and her unaffected sister III:5 share the same maternal haplotype.

Figure 3.

Pedigrees of newly ascertained LFSNHL families. Shaded symbols indicate those affected with LFSNHL. Open symbols indicate normal hearing. (A) Family W. autosomal dominant LFSNHL. (B) Family 35, autosomal dominant LFSNHL. (C) Family 19. (D) Family 21. Arrow denotes proband.?, audiometric data not available.

Figure 4.

SSCP analysis of WFS1 exon 8–7 in Family 59. Lanes 1–9, affected family members; lanes 10–15, unaffected family members; lane 16, normal control. Note variant indicated by asterisk common to all affected family members but not seen in unaffected family members or control. Note also two distinct SSCP patterns in upper bands associated with the single nucleotide polymorphism 2735G→A (accession no. AF084481). Lane 1 shows the typical pattern associated with 2735G→A, whereas lane 16 shows the typical pattern associated with the wild-type

Figure 5.

Chromatograms demonstrating mutations in five families with LFSNHL. All chromatograms are from sequencing of forward strand. (A) Sequence from control showing wild-type nucleotide T at position 2656. The wild-type amino acid 829 is leucine. (B) Sequence of an affected individual from Family 59, showing the 2656T→C mutation. Note overlapping peaks (asterisk) indicating heterozygous mutation in comparison to the single peak in control (asterisk) shown in Figure 4A. The wild-type codon (CTG) is shown above the mutated codon (CCG). (C) Sequence of an affected individual from Family 19. Note overlapping peaks (asterisk) demonstrating the heterozygous mutation 2662G→A. (D) Sequence analysis of Family 21 demonstrating overlapping peaks (asterisk) indicative of the 2505G→A mutation. (E) Sequence analysis of an affected individual from Family T showing overlapping peaks (asterisk) indicative of the 2266C→T mutation. (F) Sequence analysis of an affected individual from Family W revealing overlapping peaks (asterisk) indicative of the 2316G→A mutation. An identical sequence change was found in Family 35 (data not shown).