Human Molecular Genetics, Vol 6, 2163-2172, Copyright © 1997 by Oxford University Press
MM Carrasquillo, J Zlotogora, S Barges and A Chakravarti
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.
ARTICLES
Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations
Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine, Cleveland OH 44106, USA.
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