A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q

被引:303
作者
Shiels, A
Mackay, D
Ionides, A
Berry, V
Moore, A
Bhattacharya, S
机构
[1] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, Cataract Res Ctr, St Louis, MO 63110 USA
[2] Inst Ophthalmol, Dept Mol Genet, London, England
[3] Moorfields Eye Hosp, London, England
基金
英国惠康基金;
关键词
D O I
10.1086/301762
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
CZP1, a locus for autosomal dominant "zonular pulveruleut" cataract, previously had been linked with the Duffy blood-group-antigen locus on chromosome Iq, Here we report genetic refinement of the CZP1 locus and 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 original Ev, pedigree, which now spans eight generations. Significantly positive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Z(max)] = 4.52; maximum recombination frequency [theta(max)] = 0) and D1S514 (Z(max) = 4.48; theta(max) = 0), Multipoint analysis 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 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 so 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.
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页码:526 / 532
页数:7
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