Correspondence

Connexin 26 R143W Mutation Associated with Recessive Nonsyndromic Sensorineural Deafness in Africa

N Engl J Med 1998; 338:548-550February 19, 1998

Article

To the Editor:

Recently, the pathologic process underlying nonsyndromic forms of inherited hearing impairment has been studied at the molecular level.1 The previously localized DFNA3 and DFNB1 loci, which are associated with nonsyndromic deafness of dominant and recessive inheritance, have in white families been attributed to sense (M34T) and nonsense (W24X or W77X) mutations, respectively, of the gene encoding the gap-junction protein connexin 26 (Cx26 ).1

We describe a different mutation of the Cx26 gene in several families in a village in eastern Ghana known nationwide for having an extraordinarily high prevalence of profound nonsyndromic hearing impairment.2 A linkage analysis that included 29 subjects from 6 families revealed a lod score of 4.5 at marker position D13S175, corresponding to the known DFNB1 locus on chromosome 13q11 (data not shown). Sequencing of the Cx26 coding region in 21 deaf subjects from 11 families revealed in all of them a homozygous mutation in which T was substituted for C in the first position of codon 143, resulting in the nonconservative amino acid exchange of a tryptophan for an arginine residue (Figure 1AFigure 1Audiograms and DNA Sequences. and Figure 1B). Twelve heterozygous family members were identified; all of them had normal hearing, which was documented in nine by audiometric examinations (Figure 1A and Figure 1B).

Connexin 26 is a transmembrane protein expressed in several structures lining the cochlear duct.3,4 By undergoing oligomerization into hexamers, it forms transmembrane toroid structures that fuse to generate intercellular communication channels, which allow the cell-to-cell diffusion of small molecules such as inorganic ions.3 The previously identified M34T mutation is dominant 1; it therefore appears to alter the structure of connexin 26 in such a way that in heterozygotes, mutant copies of connexin 26 inhibit their wild-type counterparts.3 Since the R143W mutant described here causes a recessive form of disease, its presence does not appear to impair the function of the wild-type molecule in heterozygotes.

It was of interest to see that among the families in our study, the disease haplotypes differed greatly (data not shown), indicating that the mutation arose at least 60 generations ago.5 This finding underlines the stability of the village community studied, and in addition, it shows that the mutation has had several centuries to spread into surrounding populations and possibly across the ocean.

George W. Brobby, M.D.
University of Science and Technology, Kumasi, Ghana

Bertram Müller-Myhsok, M.D.
Rolf D. Horstmann, M.D.
Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany

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