A Missense Mutation in the Human Connexin50 Gene (GJA8) Underlies Autosomal Dominant 'Zonular Pulverulent' Cataract, on Chromosome 1q

7 páginas, 3 figuras, 2 tablas.-- The results of this study were presented in part at the 47th annual meeting of The American Society of Human Genetics, October 28–November 1, 1997, in Baltimore.-- et al.
CZP1, a locus for autosomal dominant “zonular pulverulent” cataract, previously had been linked with the Duffy blood-group–antigen locus on chromosome 1q. Here we report genetic refinement of the CZP1 locus and show that the underlying mutation is present in GJA8, the gene for connexin50. To map the CZP1 locus we performed linkage analysis using microsatellite markers on two distantly related branches of the original Ev. pedigree, which now spans eight generations. Significantly positive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Zmax] = 4.52; maximum recombination frequency [θmax] = 0) and D1S514 (Zmax = 4.48; θmax = 0). Multipoint analysis gave Zmax = 5.22 (θmax = 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 of the GJA8 gene from the pedigree detected a C→T transition in codon 88, which introduced a novel MnlI restriction-enzyme site that also cosegregated with the cataract. This missense mutation is predicted to result in the nonconservative substitution of serine for a phylogenetically conserved proline (P88S). These studies provide the first direct evidence that GJA8 plays a vital role in the maintenance of human lens transparency and identify the genetic defect believed to underlie the first inherited disease to be linked to a human autosome.
This work is supported Wellcome Trust grant 043073/Z/94/Z, NIH grants EY02687 and EY11411, and by Research to Prevent Blindness, Inc. A.I. is supported by a grant from the Friends of Moorfields Eye Hospital, and D.M. is a Wellcome Prize Student.