Connexin46 mutations in autosomal dominant congenital cataract

Donna Mackay, Alexander Ionides, Zoha Kibar, Guy Rouleau, Vanita Berry, Anthony Moore, Alan Shiels, Shomi Bhattacharya

Research output: Contribution to journalArticlepeer-review

258 Scopus citations


Loci for autosomal dominant 'zonular pulverulent' cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein α-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Z(max)] => 7.0; maximum recombination frequency [θ(max)] = 0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared ~88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A→G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.

Original languageEnglish
Pages (from-to)1357-1364
Number of pages8
JournalAmerican journal of human genetics
Issue number5
StatePublished - 1999


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