A Danish family with juvenile onset of optic atrophy and associated hearing impairment was investigated. Haplotype and sequence analysis excluded mutations in OPA1
, and GJB6
. A positive LOD score of Z
1.61 for 4p16.3 followed by sequencing of the WFS1
gene led to identification of a novel WFS1
missense mutation, E864K.
Four individuals carrying this mutation had optic atrophy and hearing impairment. The three with the most extended observation periods (III:3, IV:4, V:3) presented initially with a pure sensorineural moderate hearing impairment with shallow mid frequency U‐shaped audiograms (fig 2, tables 2 and 3). The hearing impairment was progressive, becoming moderate to severe with flat or gently sloping audiogram configurations. The hearing impairment found in other family members was phenotypically different. In III:5 and III:7, the hearing impairment was age related, presenting in old age. The profound congenital hearing impairment in IV:12 and the more moderate deeply U‐shaped hearing loss in her brothe (IV:11) are so far unexplained, as we excluded mutations in the coding regions of GJB2, and GJB6.
The type of hearing impairment in V:3, IV:6, IV:4, and III:3 significantly affected the lower frequencies, although only in IV:6 did they fulfill the stringent definition of LFSNHL.
The metabolic examinations of three individuals with the WFS1 mutation revealed that two of them had overt but undiagnosed diabetes (IV:6) or impaired glucose tolerance (IV:4) and that two mutation carriers (IV:6 and V:3) had impaired insulinogenic index. Thus, these data of impaired glucose regulation indicate that the WFS1 mutation may affect the pancreatic β‐cell function as well.
Altogether, at least 20 different missense mutations in WFS1
have been reported to associate with autosomal dominant LFSNHL; 19 in exon 8 and 1 in exon 5.30,31
Seventeen cluster in the C‐terminus of the WFS1 protein, one is located in the transmembrane domain 9, one in the cytoplamatic domain 5, and one sporadic case in the N‐terminus.20,21,32,33
It is well known that mutations in the WSF1
gene can cause variable expression, giving rise to different clinical complications such as hearing, vision, diabetes, and depression. In a large non‐syndromic autosomal dominant LFSNHL family reported by Young et al21
, one individual who was homozygous for a A716T mutation in the C‐terminus had partial WS features (diabetes mellitus from 3 years of age, 20–30 dB HL in the frequency range 0.5–4 kHz and cataract, but normal renal ultrasound and no optic atrophy).21
These findings clearly demonstrate that access to in vitro functional tests of the WFS1 protein is crucially wanted in order to assess the implications of the individual mutations.
In conclusion, this is the first report of a missense mutation (c.2590G→A, E864K) in the WFS1 gene in a family with ADOA in combination with hearing impairment. This mutation changes the C‐terminus of the protein by substitution of the non‐charged amino acid glutamine by the positively charged lysine and is predicted to causes a critical change of the part of the WFS1 protein that is at the endoplasmic reticulum lumen. The glutamine E864 is conserved in the WFS1 protein in human, mouse, rat, chimpanzee, and chicken (fig 3C), supporting our interpretation that the mutation is causative. Our findings illustrate that mutations in WFS1 may be associated with a broader clinical spectrum of phenotypes than previously reported, in terms of ADOA, impaired glucose regulation, and audiological characteristics. The increasing recognition of different inheritance patterns and the spectrum of a broad clinical presentation associated with mutations in the OPA1, OPA3, and WFS1 genes are striking. Such observations warrant a strong awareness of the possibility of multiple organs being affected in patients seen by both ophthalmologists and audiologists. Through meticulous characterisation of the clinical implications of mutations in these genes, we may obtain a deeper understanding of the normal biological functions of WSF1 as well as other candidate genes involved in hearing and vision disorders.