Connexin26 mutations associated with the most common form of non- syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans

Abstract

Non-syndromic neurosensory autosomal recessive deafness (NSRD) is the most common form of genetic hearing loss. Previous studies defined at least 15 human NSRD loci. Recently we demonstrated that DFNB1, located on the long arm of chromosome 13, accounts for approximately 80% of cases in the Mediterranean area. Further analysis with additional markers now identifies several recombinants which narrow the candidate region to approximately 5 cM, encompassed by markers D13S141 and D13S232 and including several ESTs and candidate genes, including the connexin26 (GJB2) gene. Analysis of PCR products from our affected patients' DNA shows two frameshift mutations in the connexin26 gene. Deletion of a G within a stretch of six Gs at position 35 of the GJB2 cDNA (mutation 35delG) leads to premature chain termination and is present in 63% of NSRD chromosomes, demonstrating linkage to chromosome 13. Deletion of a T at position 167 of GJB2 (mutation 167delT), also resulting in premature chain termination, was detected in another patient. Four neutral sequence polymorphisms were also identified. These findings are in agreement with a recent study showing that mutations in the connexin26 gene are associated with genetic forms of deafness in three Pakistani families and that GJB2 is DFNB1. Connexin26 is a member of a large family of proteins involved in formation of gap junctions, which are involved in electrical synapses and the direct transfer of small molecules and ionic currents between neighboring cells. The identification of GJB2 as the DFNB1 gene should provide a better understanding of the biology of normal and abnormal hearing, help form the basis for diagnosis and may facilitate development of strategies for treatment of this common genetic disorder.

Methodology of a multistate study of congenital hearing loss: Preliminary data from Utah newborn screening

“…Approximately 12% of these individuals were identified as having mutations in the GJB2 gene responsible for the hearing loss. This frequency is lower than previously reported frequencies, suggesting a unique population, small numbers, or that the frequency in newborn samples may be lower because the study included milder cases [Denoyelle et al, 1997;Zelante et al, 1997]. The discrepancy in frequency of GJB2 mutations in these studies underscores the need for further study and proper classification of cases.…”

“…To date, 79 loci for nonsyndromic hearing loss have been identified: 40 autosomal dominant, 34 autosomal recessive, and 5 X-linked [Hereditary Hearing Loss Homepage, 2003]. Multiple studies have shown that mutations in the single GJB2 gene may account for up to 50% of nonsyndromic sensorineural autosomal recessive hearing loss or 20% of all childhood hearing loss [Denoyelle et al, 1997;Zelante et al, 1997;Cohn et al, 1999;Green et al, 2002]. The GJB2 gene encodes the connexin 26 protein, which is involved in gap junction formation allowing cell-to-cell diffusion and the transfer of ions between neighboring cells.…”

“…The GJB2 gene encodes the connexin 26 protein, which is involved in gap junction formation allowing cell-to-cell diffusion and the transfer of ions between neighboring cells. The 35delG mutation (previously described as the 30delG mutation) accounts for the majority ($70%) of the GJB2 mutant alleles in Caucasians [Denoyelle et al, 1997;Zelante et al, 1997], contributing significantly to autosomal recessive congenital hearing loss. Based on an extensive review of the literature on the frequency of GJB2 mutations in different populations, Kenneson et al [2002] estimated the carrier frequency of the 35delG mutation in the Caucasian, Northern European population as being 1-3%.…”

The Iranian Human Mutation Gene Bank: A data and sample resource for worldwide collaborative genetics research

“…It is an extremely heterogeneous disorder in which at least 30 reported loci [Van Camp et al, 1997;Zbar et al, 1998;Keats and Berlin, 1999] and mutations in one gene (GJB2) have been shown to be major cause of ARNSD in many different populations [Maw et al, 1995;Gasparini et al, 1997;Kelsell et al, 1997;Park et al, 2000;Morell et al, 1998;Zelante et al, 1997]. We have studied the mutation load of GJB2 in the Iranian population and have found the prevalence to be much lower than in other studied populations (Najmabadi et al, 2001; submitted manuscript).…”

Correlação entre dados audiométricos e mutação 35delG em dez pacientes

“…This nucleotide deletion can occur at position 35 (35delG) or at position 30 (30delG) of the gene, but the deletion at position 35 (35delG), genetically related to chromosome 13, is the more frequent one, varying between approximately 50% to 85% of the non-syndromic deafness cases in patients from Italy, Spain, and Israel 7,[11][12][13] . In a study with Brazilian patients14, mutations in gene GJB2 were found in 22% of families tested with at least one patient with hearing loss, and in 11.5% of cases in which an environmental etiology was not completely ruled out.…”