Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss
- Mark J Housemana,
- Lucy A Ellisb,
- Alistair Pagnamentac,
- Wei-Li Did,
- Sarah Rickardc,
- Amelia H Osborne,
- Hans-Henrik M Dahle,
- Graham R Taylorb,
- Maria Bitner-Glindziczc,
- William Reardonf,
- Robert F Muellerg,
- David P Kelselld
- aMolecular Medicine Unit, St James's University Hospital, Leeds LS9 7TF, UK, bYorkshire Regional DNA Laboratory, St James's University Hospital, Leeds LS9 7TF, UK, cClinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH and Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK, dCentre for Cutaneous Research, St Bartholomews' and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, 2 Newark Street, Whitechapel, London E1 2AT, UK, eThe Murdoch Institute, Royal Children's Hospital, Parkville 3052, Melbourne, Victoria, Australia, fNational Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland, gDepartment of Clinical Genetics, St James's University Hospital, Leeds LS9 7TF, UK
- Dr Kelsell, kelsell{at}icrf.icnet.uk
- Revised 3 November 2000
- Accepted 8 November 2000
Abstract
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.
