A novel mutation in GJA8 associated with autosomal dominant congenital cataract in a family of Indian origin.

PURPOSE To identify the genetic defect in an autosomal dominant congenital cataract family, having 15 members in three generations, affected with bilateral cataract that gave the appearance of "full moon" with Y-sutural opacities. METHODS A detailed family history and clinical data were recorded. A genome-wide scan by two point linkage analysis using nearly 400 microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bidirectional sequencing of amplified products. RESULTS A maximum two point lod score of 5.45 at theta=0.00 was obtained with marker D1S534. Haplotype analysis placed the cataract locus to a 14.1 cM region between D1S221 and D1S498, in close proximity to the gene for the gap junction channel protein connexin 50 (GJA8) at 1q21. Mutation screening in GJA8 identified a novel G>C transversion at nucleotide position c.235. This nucleotide change resulted in the substitution of highly conserved valine by leucine at codon 79 (V79L). This nucleotide substitution was neither seen in any unaffected member of the family nor in 180 unrelated control subjects (360 chromosomes) from same ethnic background tested by sequence analysis of GJA8. CONCLUSIONS The present study describes the mapping of a locus for congenital cataract that appeared like "full moon" with Y-sutural opacities at 1q21 and identifies a previously unreported mutation in GJA8. These findings thus expand the mutation spectrum of GJA8.