title: Compound heterozygosity for dominant and recessive GJB2 mutations: effect on phenotype and review of the literature.
abstract: Mutations in GJB2 (which encodes the gap-junction protein connexin 26) are the most common cause of genetic deafness in many populations. To date, more than 100 deafness-causing mutations have been described in this gene. The majority of these mutations are inherited in an autosomal recessive manner, but approximately 19 GJB2 mutations have been associated with dominantly inherited hearing loss. One, W44C, was first identified in two families from France. We subsequently described a family in the United States with the same mutation. In these families, W44C segregates with a dominantly inherited, early-onset, progressive, sensorineural deafness that is worse in the high frequencies. Since that report, we have tested additional family members and identified two siblings who are compound heterozygous for the W44C and K15T mutations. Their father, the original proband, is heterozygous for the dominant W44C mutation, and their mother is compound heterozygous for two recessively inherited mutations, K15T and 35delG. Both children have a profound, sensorineural deafness and use manual communication, in contrast to their parents and other relatives whose hearing losses are less severe and who can communicate orally. The difference in phenotype may be a result of the disruption of different functions of the gap-junction protein by the two mutations, which have an additive effect.
authors: Department of Biology, Gallaudet University, Washington, District of Columbia 20002, USA. katherine.welch@gallaudet.edu
authors: Katherine O
authors: KO
authors: Welch
authors: Ruth S
authors: RS
authors: Marin
authors: Arti
authors: A
authors: Pandya
authors: Kathleen S
authors: KS
authors: Arnos
mesh_terms: D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005602:France; D005787:Gene Frequency; D005799:Genes, Dominant; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26