Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT

Previous studies of the gap-junction beta-2 subunit gene GJB2 (connexin 26) have suggested that the 101T-->C (M34T) nucleotide substitution may be a m utant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-j unction assembly of the M34T allele product expressed in Xenopus oocytes an d HeLa cells. The results of our current study of a family cosegregating th e 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this ph enotype did not cosegregate with the compound-heterozygous genotype M34T/16 7delT. Since 167delT is a null allele of GJB2, this result indicates that t he in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observatio n raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importanc e of observing cosegregation with deafness in large families to confirm tha t these missense alleles are mutant DFNB1 alleles.