The contribution of GJB2 (Connexin 26) 35delG to age-related hearing impairment and noise-induced hearing loss
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. Ontology & Neurotology
(Impact Factor: 1.79).
11/2007; 28(7):970-5. DOI: 10.1097/MAO.0b013e3180dca1b9
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.
Available from: Pei-Jer Chen
- "It is important to note, that the allele frequency of GJB4 p.C169W is approximately 3% in the general population, which is, to some extent, higher than the convention definition of a mutation, i.e., the allele frequency of a mutation should be less than 1% . It has been demonstrated that the allele frequencies of several common deafness mutations are higher than 1% in the general population, e.g., GJB2 p.V37I (∼10% in some East Asian general populations) , , c.235delC (∼1.5% in the Chinese general population) , and c.35delG (∼1.3% in the European general population) . However, all these mutations are recessive. "
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ABSTRACT: Despite the clinical utility of genetic diagnosis to address idiopathic sensorineural hearing impairment (SNHI), the current strategy for screening mutations via Sanger sequencing suffers from the limitation that only a limited number of DNA fragments associated with common deafness mutations can be genotyped. Consequently, a definitive genetic diagnosis cannot be achieved in many families with discernible family history. To investigate the diagnostic utility of massively parallel sequencing (MPS), we applied the MPS technique to 12 multiplex families with idiopathic SNHI in which common deafness mutations had previously been ruled out. NimbleGen sequence capture array was designed to target all protein coding sequences (CDSs) and 100 bp of the flanking sequence of 80 common deafness genes. We performed MPS on the Illumina HiSeq2000, and applied BWA, SAMtools, Picard, GATK, Variant Tools, ANNOVAR, and IGV for bioinformatics analyses. Initial data filtering with allele frequencies (<5% in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFT scores (>0.95) prioritized 5 indels (insertions/deletions) and 36 missense variants in the 12 multiplex families. After further validation by Sanger sequencing, segregation pattern, and evolutionary conservation of amino acid residues, we identified 4 variants in 4 different genes, which might lead to SNHI in 4 families compatible with autosomal dominant inheritance. These included p.R75Q, p.T381M, p.S680F, and p.E1256K. Among them, p.S680F and p.E1256K were novel. In conclusion, MPS allows genetic diagnosis in multiplex families with idiopathic SNHI by detecting mutations in relatively uncommon deafness genes.
PLoS ONE 02/2013; 8(2):e57369. DOI:10.1371/journal.pone.0057369 · 3.23 Impact Factor
Available from: smu.edu.cn
- "Another study , using a Polish sample set, concluded that the role of the GJB2 c.35delG mutation as a determining factor in noise susceptibility is negligible. However, both studies were performed in different sample sets – Van Eyken et al.  analyzed Caucasians samples with an age range of 53–67 years, originating from 7 countries and Polish workers exposed to occupational noise; while Carlsson et al.  performed this analysis in the Swedish population . Van Laer et al.  detected that the variation in genes involved in coupling of cells and potassium recycling in the inner ear such as KCNE1, KCNQ1 and KC- NQ4 might partly explain the variability in susceptibility to noise. "
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ABSTRACT: To investigate whether single nucleotide polymorphisms (SNPs) in the Mn-superoxide dismutase gene (SOD2) underlie the susceptibility to noise-induced hearing loss (NIHL).
Audiometric data from 2400 Chinese Han workers who exposed to occupational noise were analyzed. DNA samples were collected from the 10% most susceptible and the 10% most resistant individuals, and five SNPs (SOD2 rs2842980, rs5746136, rs2758331, rs4880 and rs5746092) were genotyped by Taqman SNP Genotyping Kits. The SNP main effects and interactions between noise exposure and SNP were analyzed using logistic regression. Haplotypes were analyzed by using Haploview software.
The CT genotype of rs4880 (SOD2 V16A SNP) was associated with a higher risk of NIHL (covariates-adjusted OR, 2.18; 95% CI, 1.34-3.54, P=0.002). Haplotype analysis revealed that the frequency of AGCCG at the five SNP loci was significantly higher in the susceptible group (P=0.020). With AGCTG as the reference, the OR (95% CI) was 2.63 (1.14, 6.06). The rs4880 polymorphisms imposed larger effects when the carriers were exposed to higher levels of noise, indicating the interaction between SNP and noise exposure.
Our results suggest that SOD2 V16A SNP in the mitochondrial targeting sequence is associated with noise induced hearing loss in Chinese workers, and this effect was enhanced by higher levels of noise exposure.
Disease markers 06/2010; 28(3):137-47. DOI:10.3233/DMA-2010-0693 · 1.56 Impact Factor
Available from: tau.ac.il
- "Traditionally, this has been studied in animal models, but over the last few years, several studies have been performed using audiometric data from populations of noise-exposed workers, in conjunction with genotyping of single nucleotide polymorphisms (SNPs). There seems to be no association between the most prevalent connexin 26 (GJB2) mutation, 35delG and NIHL, at least in a study performed in a population of workers exposed to noise (Van Eyken et al, 2007). Oxidative stress may be a complicating factor in NIHL because an association was found for a few genes that protect against oxidative stress (reviewed in Konings et al, 2009). "
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ABSTRACT: Sitting in the rainforest in Costa Rica, you can hear rain, rushing water, howling monkeys, birds and crickets. All are in abundance and although they are tantalizing to all your senses, your sense of hearing picks up what you cannot see with your eyes or feel with your hands.
EMBO Molecular Medicine 05/2009; 1(2):85-7. DOI:10.1002/emmm.200900016 · 8.67 Impact Factor
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