Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations.
Non-syndromic recessive deafness (NSRD) is the most common form of prelingual hereditary hearing loss. To date, 10 autosomal NSRD loci (DFNBs) have been identified by genetic mapping; at least three times as many additional loci are expected to be identified. We have performed linkage analyses in two inter-related inbred kindreds, comprised of >50 affecteds, from a single Israeli-Arab village segregating NSRD. Genetic mapping by two-point and multi-point linkage analysis in 10 candidate regions identified the segregating gene to be on human chromosome 13q11 (DFNB1). Haplotype analysis, using eight microsatellite markers spanning 15 cM in 13q11, suggested the segregation of two different mutations in this kindred: affected individuals were homozygotes for either haplotype or compound heterozygotes. The gene for the connexin 26 gap junction protein, recently shown to be mutant in both dominant and recessive deafness, maps to this locus. We identified two distinct mutations, W77R and Gdel35, both of which likely inactivate connexin 26. The Gdel35 change likely occurs at a mutational hotspot within the connexin 26 gene. The recombination of marker alleles at the polymorphisms studied in 13q11, at known map distances from the mutations, allowed us to estimate the age of the mutations to be 3-5 generations (75-125 years). This study independently confirms the identity of connexin 26 as an NSRD gene. Importantly, we demonstrate that in small populations with high rates of consanguinity, as compared with large outbred populations, recessive mutations may have very recent origin and show allelic diversity.
Carrasquillo
M M
MM
Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine, Cleveland OH 44106, USA.
Zlotogora
J
J
Barges
S
S
Chakravarti
A
A
D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D003241:Consanguinity; D003638:Deafness / Q000235:genetics*; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D010375:Pedigree
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26