In the present study, we used WES to successfully identify a mutation in WFS1 causing the autosomal dominant type of sensorineural hearing loss.
To date, more than 250 mutations in the WFS1 gene have been reported worldwide (http://www.hgmd.cf.ac.uk/ac/index.php). Mutations in the WFS1 gene are responsible for both Wolfram syndrome and autosomal dominant, nonsyndromic hearing loss (DFNA6/14/38) [1, 8, 9]. Wolfram syndrome is an autosomal recessive type disorder associated with diabetes mellitus, diabetes insipidus, optic atrophy, and hearing loss. In nonsyndromic hearing loss, DFNA6/14/38 leads to LF-NSHL. According to the literature, there are two known genes responsible for low-frequency hearing loss: DIAPH1 and WFS1 [7]. Mutations in DIAPH1 lead to progressive hearing loss and profound bilateral deafness involving all frequencies. However, mutations in WFS1 cause progressive hearing loss, but only at low frequencies and not until profound hearing loss in the case of nonsyndromic hearing loss [10, 11]. In the present study, p.S807R was also associated with LF-NSHL, with moderate severity at 60 dB HL. This audiological feature is unique only in hearing loss associated with mutations in WFS1; thus, screening of WFS1 is a reasonable first step in cases of suspected LF-NSHL without progression to a profound level.
Our description of the p.S807R (c.2419A → C) mutation in WFS1 is the second report of a mutation associated with LF-NSHL in Korean patients; the first report was the p.V412A mutation in WFS1 [12]. Although there are more than 250 mutations in WFS1, some rare mutations have been identified in multiple independent families. In addition, there are only two mutations that span two different ethnic backgrounds: European (p.A716T) and Japanese (p.E864K) [10]. p.S807R was previously reported in a family from the United Kingdom [8]; however, this study is the first to identify and report the mutation in an East-Asian individual. Interestingly, all mutations found in both ethnicities (European and East Asian, including p.A716T, p.E864K, and p.S807R) are located in exon 8, which encodes the C-terminal intracytoplasmic domain. This finding indicates that these mutations may be “hot spot” mutations in exon 8 that span different ethnicities. To convincely tell the mutation is a founder mutation (the result of admixture of two ethnics) or a hot spot, it would be helpful to to compare haplotypes of our patients and British patients.
The majority of mutations associated with LF-NSHL are, in fact, missense mutations located in exon 8, whereas those linked to Wolfram syndrome are frameshift and nonsense mutations [7, 8, 10]. The mutations responsible for LF-NSHL do not inactivate WFS1 and are presumed to have a dominant-negative effect on the normal WFS1 protein, consistent with an autosomal dominant type of inheritance. Because the S807 residue is located in the C-terminal domain, the missense mutation at p.S807R affects only a limited number of functions. Although the physiological role of WFS1 in the inner ear remains unknown, mutations, such as p.S807R, only partially disrupt the function of WFS1; thus, hearing loss may not necessarily progress to profound deafness.
Mutations in WFS1 are associated with LF-NSHL. Given that p.S807R was previously found in individuals of European ethnicity, p.S807R may be a hot-spot mutation in WFS1. Because the majority of mutations in WFS1 associated with LF-NSHL are located in exon 8, screening exon 8 should be considered first in genetic analyses of patients with LF-NSHL.