A MISSENSE MUTATION IN THE HUMAN CONNEXIN50 GENE (GJA8) UNDERLIES AUTOSOMAL-DOMINANT ZONULAR PULVERULENT CATARACT, ON CHROMOSOME 1Q

CZP1, a locus for autosomal dominant ''zonular pulveruleut'' cataract, previously had been linked with the Duffy blood-group-antigen locus o n chromosome Iq, Here we report genetic refinement of the CZP1 locus a nd show that the underlying mutation is present in GJA8, the gene for connexin50. To mag the CZP1: focus we performed linkage analysis using microsatellite markers on two distantly related branches of the origi nal Ev, pedigree, which now spans eight generations. Significantly pos itive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Z(max)] = 4.52; maximum recombination frequency [theta(ma x)] = 0) and D1S514 (Z(max) = 4.48; theta(max) = 0), Multipoint analys is gave Z(max) = 5.22 (theta(max) = 0) at marker D1S2669. Haplotyping indicated that CZP1 probably lies in the genetic interval D1S2746-(20. 6 cM)-D1S2771. Sequence analysis of the entire protein-coding region o f the GJA8 gene from the pedigree detected a C-->T transition in codon 88, which introduced a novel MnlI restriction-enzyme site that also c osegregated with the cataract, This missense mutation is predicted so result in the nonconservative substitution of serine for a phylogeneti cally conserved proline (P88S). These studies provide the first direct evidence that GJA8 plays a vital role in the maintenance of human len s transparency and identify the genetic defect believed to underlie th e first inherited disease to be linked to a human autosome.