Abstract
BackgroundLow 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.MethodsThe 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.ResultsSequence 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.ConclusionWe 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.
Highlights
Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding
We discovered a novel heterozygous missense mutation in exon 8 of Wolfram syndrome type 1 gene (WFS1) predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family
We describe vestibular evoked myogenic potentials (VEMP) and EcochG findings for individuals segregating a heterozygous WFS1 mutation
Summary
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. Over 90 different genetic loci have been linked to hereditary auditory impairment [1] The majority of these loci are associated with high frequency hearing (page number not for citation purposes). BMC Medical Genetics 2008, 9:48 http://www.biomedcentral.com/1471-2350/9/48 loss or a deficit affecting all frequencies, with only four loci linked to low frequency hearing loss. Non-syndromic autosomal dominant low frequency sensorineural hearing loss (LFSNHL) has been mapped to the DFNA1, DFNA11, DFNA54, and DFNA6/14/38 loci. These four loci are described by the letters DFN, which stand for deafness, and the letter A to indicate autosomal dominant inheritance. The fourth and most common locus for LFSNHL is DFNA6/14/38, which results from heterozygous mutations in the Wolfram syndrome type 1 gene (WFS1) [5,6,7]
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