Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss

Mutations in the GJB3 gene encoding connexin31 (Cx31) can cause a dominant non-syndromic form of hearing loss (DFNA2), To determine whether mutations at this locus can also cause recessive non-syndromic deafness, we screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Th e three affected individuals in the two families were born to nonconsanguin eous parents and had an early onset bilateral sensorineural hearing loss. I n both families, differing SSCP patterns were observed in affected and unaf fected individuals. Sequence analysis in both families demonstrated an in-f rame 3 bp deletion (423-425delATT) in one allele, which leads to the loss o f an isoleucine residue at codon 141, and a 423A-->G transversion in the ot her allele, which creates an Ile-->Val substitution at codon 141 (I141V), N either of these two mutations was detected in DNA from 100 unrelated contro l subjects. The altered isoleucine residue lies within the third conserved a-helical transmembrane domain (M3), which is critical for the formation of the wall of the gap junction pore. Both the deletion of the isoleucine res idue 141 and its substitution to valine in the two families could alter the structure of M3, and impair the function of the gap junction. The present data demonstrate that, like mutations in connexin26, mutations in Cx31 can lead to both recessive and dominant forms of nonsyndromic deafness.