Nonsense mutation in the CRYBB2 gene causing autosomal dominant progressive polymorphic congenital coronary cataracts

PURPOSE We sought to identify the genetic defect in a large, five-generation Chinese family with autosomal dominant progressive polymorphic congenital coronary cataracts and to examine the clinical features in detail. METHODS Clinical and ophthalmologic examinations were conducted on family members. All members were genotyped with microsatellite markers at loci previously associated with cataracts. Two-point LOD scores were calculated using a linkage package after genotyping. A mutation was detected by direct sequencing and verified by denaturing high-performance liquid chromatography (DHPLC). RESULTS Clinical observations showed that all affected family members had progressive polymorphic coronary cataracts. Linkage analysis was obtained at markers, D22S303 (LOD score [Z]=2.11, recombination fraction [theta]=0.0) and D22S1167 (Z=1.20, theta=0.0). Haplotype analysis indicated that the cataract gene was closely linked with these two markers. Sequencing the betaB-crystallin gene (CRYBB2) revealed a C --> T transition in exon 6, which changed a codon from Gln to a stop codon (P.Q155X). This mutation cosegregated with all affected individuals and was not observed in any unaffected family member or 100 normal, unrelated individuals. CONCLUSIONS This study identified a mutation in CRYBB2 in a large Chinese family with autosomal dominant progressive polymorphic congenital coronary cataracts. These results provide evidence that CRYBB2 is a pathogenic gene for congenital cataracts; at the same time, congenital cataracts are a clinically and genetically heterogeneous lens condition.