PURPOSE: To identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataract. METHODS: Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci associated with cataracts. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. RESULTS: Linkage analysis was obtained at markers D1S1653 (LOD score [Z] = 1.50, recombination fraction [theta] = 0.0) and D1S498 (LOD score Z = 0.90, recombination fraction [theta] = 0.0), which encompasses the connexin 50 gene (GJA8). Sequencing the coding regions of GJA8 revealed a novel, heterozygous c.773C > T transition that resulted in the substitution of a highly conserved serine by phenylalanine at codon 258 (S258F). Bioinformatics analysis showed that the mutation altered the hydrophobicity and secondary structure of the protein. This mutation co-segregated with the disease phenotype in all affected individuals and was not found in the unaffected family members or in 100 normal unrelated individuals. CONCLUSIONS: This study has identified a novel missense mutation located in the carboxyl terminus of GJA8 (S258F) associated with autosomal dominant nuclear cataract.
PURPOSE: To identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataract. METHODS: Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci associated with cataracts. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. RESULTS: Linkage analysis was obtained at markers D1S1653 (LOD score [Z] = 1.50, recombination fraction [theta] = 0.0) and D1S498 (LOD score Z = 0.90, recombination fraction [theta] = 0.0), which encompasses the connexin 50 gene (GJA8). Sequencing the coding regions of GJA8 revealed a novel, heterozygous c.773C > T transition that resulted in the substitution of a highly conserved serine by phenylalanine at codon 258 (S258F). Bioinformatics analysis showed that the mutation altered the hydrophobicity and secondary structure of the protein. This mutation co-segregated with the disease phenotype in all affected individuals and was not found in the unaffected family members or in 100 normal unrelated individuals. CONCLUSIONS: This study has identified a novel missense mutation located in the carboxyl terminus of GJA8 (S258F) associated with autosomal dominant nuclear cataract.