The M34T Allele Variant of Connexin 26

Abstract

GJB2 encodes the protein Connexin 26, one of the building blocks of gap junctions. Each Connexin 26 molecule can oligomerize with five other connexins to form a connexon; two connexons, in turn, can form a gap junction. Because mutations in GJB2 are the most common cause of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss, the effect of the Connexin 26 allele variants on this dynamic 'construction' process and the function of any gap junctions that do form is particularly germane. One of the more controversial allele variants, M34T, has been hypothesized to cause autosomal dominant nonsyndromic hearing loss. In this paper, we present clinical and genotypic data that refutes this hypothesis and suggests that the effect of the M34T allele variant may be dependent on the mutations segregating in the opposing allele.

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

“…The similar prevalence of the M34T between the deaf and the hearing population observed in this report and in other 18 is in favor of the absence of pathogenic effect of this variant. The frequency of the M34T allele in the French control population reported here (1.72%) is consistent with prevalence found in other populations: 25 1.5% in the USA, 8 2.4% in Belgium, 26 1.98% in the UK, 11 1.33% in the Grampian region.…”

“…12,11,18,10,23,13,24 However, as Griffith et al 10 we reported here five normal hearing subjects carrying a compound heterozygous mutation in which the M34T substitution is associated in trans with a truncated mutation : the 35delG GJB2 mutation or the (GJB6-D13S1830)del. 20 These results indicate that M34T is not a recessive mutation responsible for hearing loss.…”

“…Moreover, Cucci report two brothers presenting with the same hearing defect with different genotypes: two siblings carrying the same genotype, but with defects of different severity. 18 All these observations are not consistent with a variant role of M34T according to the mutation segregating on the opposite allele. Two recent reports have found a 10 base pairs deletion in the 5 0 UTR of GJB2 that occurs together with the M34T mutation.…”

“…20 These results indicate that M34T is not a recessive mutation responsible for hearing loss. Cucci et al 18 proposed that the effect of the M34T allele may be dependent on the mutation present in trans. However, his hypothesis could not explain the absence of hearing defect in the case of a segregation with frameshift mutations.…”

“…14 -16 However, others and we have reported normal hearing subjects carrying a compound heterozygous mutation:M34T/ 35delG. 10,17 Furthermore, Cucci et al 18 argue that the M34T allele variant may be dependent on the mutations segregating in the opposite allele. The M34T substitution was also implicated in the phenotypic expression of association of a palmoplantar keratoderma (PPK) with deafness 7 (MIM 124500).…”