The contribution of GJB2 (Connexin 26) 35delG to age-related hearing impairment and noise-induced hearing loss.
ABSTRACT The common GJB2 (Connexin 26) 35delG mutation might contribute to the development of age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL).
GJB2, a gene encoding a gap junction protein expressed in the inner ear, has been suggested to be involved in the potassium recycling pathway in the cochlea. GJB2 mutations account for a large number of individuals with nonsyndromic recessive hearing loss, with 35delG being the most frequent mutation in populations of European origin. Other genes involved in potassium homeostasis have been suggested to be associated with ARHI and NIHL, and distortion product otoacoustic emission distortions indicative of hearing loss alterations have been found in 35delG carriers.
We genotyped 35delG in two distinct sample sets: an ARHI sample set, composed of 2,311 Caucasian samples from nine different centers originating from seven different countries with an age range between 53 and 67 years, and an NIHL sample set consisting of 702 samples from the two extremes of a noise-exposed Polish sample.
After statistical analysis, we were unable to detect an association between 35delG and ARHI, nor between 35delG and NIHL.
Our findings indicate that there is no increased susceptibility in 35delG carriers for the development of ARHI or NIHL.
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ABSTRACT: The DFNB74 locus for autosomal-recessive, nonsyndromic deafness segregating in three families was previously mapped to a 5.36 Mb interval on chromosome 12q14.2-q15. Subsequently, we ascertained five additional consanguineous families in which deafness segregated with markers at this locus and refined the critical interval to 2.31 Mb. We then sequenced the protein-coding exons of 18 genes in this interval. The affected individuals of six apparently unrelated families were homozygous for the same transversion (c.265T>G) in MSRB3, which encodes a zinc-containing methionine sulfoxide reductase B3. c.265T>G results in a substitution of glycine for cysteine (p.Cys89Gly), and this substitution cosegregates with deafness in the six DFNB74 families. This cysteine residue of MSRB3 is conserved in orthologs from yeast to humans and is involved in binding structural zinc. In vitro, p.Cys89Gly abolished zinc binding and MSRB3 enzymatic activity, indicating that p.Cys89Gly is a loss-of-function allele. The affected individuals in two other families were homozygous for a transition mutation (c.55T>C), which results in a nonsense mutation (p.Arg19X) in alternatively spliced exon 3, encoding a mitochondrial localization signal. This finding suggests that DFNB74 deafness is due to a mitochondrial dysfunction. In a cohort of 1,040 individuals (aged 53-67 years) of European ancestry, we found no association between 17 tagSNPs for MSRB3 and age-related hearing loss. Mouse Msrb3 is expressed widely. In the inner ear, it is found in the sensory epithelium of the organ of Corti and vestibular end organs as well as in cells of the spiral ganglion. Taken together, MSRB3-catalyzed reduction of methionine sulfoxides to methionine is essential for hearing.The American Journal of Human Genetics 01/2011; 88(1):19-29. · 11.20 Impact Factor
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