Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss

• Published in: Journal of medical genetics Vol. 38; no. 1; pp. 20 - 25
• Main Authors: Houseman, Mark J, Ellis, Lucy A, Pagnamenta, Alistair, Di, Wei-Li, Rickard, Sarah, Osborn, Amelia H, Dahl, Hans-Henrik M, Taylor, Graham R, Bitner-Glindzicz, Maria, Reardon, William, Mueller, Robert F, Kelsell, David P
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-01-2001; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Alleles; Amino Acid Substitution; Base Sequence; Biological and medical sciences; Chromosome Segregation; Connexin 26; Connexins - genetics; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Family Health; Female; Gene expression; Gene Frequency; Genetic Testing; Genetic Variation; Genotype; GJB2; Haplotypes; Hearing loss; Hearing Loss, Sensorineural - diagnosis; Hearing Loss, Sensorineural - genetics; Homozygote; Humans; M34T; Male; Medical sciences; Mutation; Non tumoral diseases; Original; Otorhinolaryngology. Stomatology; Pedigree; Population; Proteins; R&D; Research & development; Sequence Deletion; United Kingdom > UK; Human; Sporadic; Family study; Pathogenesis; Genetic variant; Auditory disorder; Genotype; Genetic determinism; Genetic disease; Segregation analysis; Connexin; Phenotype; Gene; Autosomal character; ENT disease; Recessive character; Perception hearing loss
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmg.38.1.20

Mutations in the human gap junction β-2 gene (GJB2) that encodes connexin-26 have been shown to cause non-syndromic sensorineural hearing loss (NSSNHL) at theDFNB1 locus on 13q11. Functional and genetic data regarding the disease causing potential of one particularGJB2 sequence variant, 101 T→C (M34T), have proven contradictory. In this study, we found the prevalence of the M34T allele in a cohort of white sib pairs and sporadic cases with NSSNHL from the United Kingdom and Ireland to be 3.179% of chromosomes screened. Significantly, we identified the first M34T/M34T genotype cosegregating in a single family with mid to high frequency NSSNHL. Screening a control population of 630 subjects we identified 25 M34T heterozygotes; however, no M34T homozygotes were detected. Surprisingly, the majority of M34T alleles (88%) were incis with a 10 bp deletion in the 5′ non-coding sequence. This non-coding deletion was also homozygous in the homozygous M34T subjects. Microsatellite analysis of flanking loci in M34T heterozygotes and controls does not define an extensive ancestral haplotype but preliminary data suggest two common alleles in subjects with the M34T allele. In summary, we provide data that support M34T acting as a recessive GJB2 allele associated with mild-moderate prelingual hearing impairment.