Connexin 26 35delG does not represent a mutational hotspot

Abstract

Non-syndromic hearing impairment (NSHI) is the most common form of deafness and presents with no other symptoms or sensory defects. Mutations in the gap junction gene GJB2 account for a high proportion of recessive NSHI. The GJB2 gene encodes connexin 26, which forms plasma membrane channels between cochlear cells. In Caucasian populations a single mutation, 35delG, accounts for most cases of NSHI. This mutation appears to be most prevalent in individuals of Mediterranean European descent, with carrier frequencies estimated as being as high as one in thirty. The 35delG region may be a mutational hotspot. The mutation arises from the deletion of a guanine from a six-guanine stretch and nearby microsatellite markers show little evidence for linkage disequilibrium. We believe that 35delG is an old mutation in a chromosomal region of high recombination. The genetic context of the 35delG mutation was examined to distinguish between an old or a recurring mutation. We identified two singlenucleotide polymorphisms (SNPs) immediately upstream of the first exon of GJB2. Polymerase chain reaction/restriction fragment length polymorphism analysis determined the SNP genotype of 35delG containing chromosomes from various populations, including Italy, Brazil, and North America. We found the same, relatively rare, polymorphism associated with the 35delG mutation in all populations studied. We have also examined microsatellite markers D13S175, which is 80 kb telomeric to GJB2, and D13S1316, which is 80 kb centromeric to GJB2. D13S175 appears to be in weak linkage disequilibrium with 35delG, while D13S1316 is less so. SNPs located between the 35delG mutation and the microsatellite markers show strong evidence of linkage disequilibrium. Taken together, these results indicate there has been substantial recombination near the 35delG mutation; however, we present evidence that the 35delG mutation arose in European and Middle Eastern populations from a single mutational event on a founder chromosome.

Haplotype Diversity and Reconstruction of Ancestral Haplotype Associated with the c.35delG Mutation in the GJB2 (Cx26) Gene among the Volgo-Ural Populations of Russia

“…However, the mechanisms of its spreading and time of appearance in the Volga-Ural region are yet to be studied. To answer these questions, we carried out a haplotypic analysis of the chromosomes carrying c.35delG and those without it, using three high-polymorphous microsatellite СА-markers: D13S175, D13S141, and D13S143 [6, 9, 10, 12, 36], which flank the locus DFNB1 containing the GJB2 gene ( Fig. 2 ).…”

“…For the analysis of the haplotypes and the estimated age of the mutation c.35delG in the GJB2 gene , three high-polymorphic microsatellite СА-markers were used: D13S175, D13S141, and D13S143 [6, 9, 10, 12, 36], flanking the DFNB1 locus, which contains the GJB2 gene. The physical and genetic localization of the markers at chromosome 13 and genetic distances between them, as well as the GJB2 gene , were identified on the basis of the Marshfield genetic linkage map (http://www.ncbi.nlm.nih.gov/mapview/).…”

“…2 ). The choice of the markers was preconditioned to fall with the strive to get the possibility of comparable data, as earlier these markers were used for the assessment of the age of mutations in the gene GJB2 in different populations [6, 9, 10, 12, 36]. …”

Evidence for single origins of 35delG and delE120 mutations in the GJB2 gene in Anatolia

“…SSCP was used afterwards for the identification of SNP1 genotypes. SNP2 (rs9552101) and SNP3 are SNP1285 and SNP 1245, respectively, that were described by Rothrock et al (12). Primers and PCR-RFLP protocols described by the same authors were used during genotyping of SNPs 2 and 3.…”

Spectrum of Genetic Changes in Patients with Non-Syndromic Hearing Impairment and Extremely High Carrier Frequency of 35delG GJB2 Mutation in Belarus

“…Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot [24], [25], while others support the theory of a common founder [26], [27]. Greece is among the countries with the highest carrier frequency of the mutation (3.5%) and, according to the idea of a common founder, the 35delG appeared about 10000 years ago in the territory of contemporary Greece and expanded throughout Europe [28], [29].…”