A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings

Abstract

Background: Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype.

Methods: The clinical phenotype of the American family was characterized by audiologic testing, vestibular evoked myogenic potentials (VEMP), and electrocochleography (EcochG) evaluation. Genetic characterization was performed by microsatellite analysis and direct sequencing of WFS1 for mutation detection.

Results: Sequence analysis of the WFS1 gene revealed a novel heterozygous mutation at c.2054G>C predicting a p.R685P amino acid substitution in wolframin. The c.2054G>C mutation segregates faithfully with hearing loss in the family and is absent in 230 control chromosomes. The p.R685 residue is located within the hydrophilic C-terminus of wolframin and is conserved across species. The VEMP and EcochG findings were normal in individuals segregating the WFS1 c.2054G>C mutation.

Conclusion: We discovered a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family. For the first time, we describe VEMP and EcochG findings for individuals segregating a heterozygous WFS1 mutation.

Figure 1

Audiologic and genetic characterization of the low frequency hearing loss pedigree. (A) Each individual in the pedigree is assigned a number. Underlined numbers indicate that auditory evaluations were performed for that person. Affected individuals are denoted by blackened symbols, males are denoted by squares, females are denoted by circles, and deceased persons are indicated by a diagonal line through the symbol. Blood drop symbols indicate individuals who donated a blood sample to the study. Symmetrical hearing loss was detected in all affected family members; therefore, only the right ear pure-tone air conduction thresholds are plotted on the audiograms. Frequency in hertz (Hz) is plotted on the x-axis and the hearing level in decibels (dB HL) on the y-axis. Plotted on each audiogram (gray line) are the average pure-tone air conduction thresholds for a person with normal hearing matched in age [39] to the family member. (B) Electropherograms showing a heterozygous c.2054G>C mutated genomic nucleotide sequence from an affected individual compared to a homozygous c.2054G unaffected family member. Nucleotide numbering starts with the ORF. (C) Protein alignment shows conservation of the p.R685 residue during evolution. The p.685P substitution in the pedigree is shown in red.