A splice site mutation in CRYBA1/A3 causing autosomal dominant posterior polar cataract in a Chinese pedigree

PURPOSE To identify the mutant gene for autosomal dominant posterior polar congenital cataract in a four-generation Chinese pedigree. METHODS The clinical data of patients from the family were recorded by slit-lamp photography. Genomic DNA samples from peripheral blood of the pedigree members were then isolated to map the relevant gene, using microsatellite markers for two-point linkage analysis. Genotype and haplotypes of the pedigree were constructed using Cyrillic software to locate the relevant region. Direct sequencing was performed to screen out the disease-causing mutation. RESULTS The congenital cataract phenotype of the pedigree was labeled as the posterior polar type by using slit-lamp photography. Linkage analysis results indicated a maximum logarithm of odds LOD score of (Z(max)) 2.02 at D17S1800 (theta(max)=0.00). Haplotyping identified a 26-cM region flanked by D17S921 and D17S800 on 17p12-21.2, namely at the betaA1/A3-crystallin (CRYBA1/A3) gene locus. Sequencing revealed a splice site mutation, G-->A, at the first base of intron 3 of CRYBA1/A3, which co-segregated with the affected individuals in the pedigree but which was not found in the unaffected members of the family or in the 50 unrelated controls. CONCLUSIONS Our results demonstrated that a splice site mutation of CRYBA1/A3 was responsible for the autosomal dominant posterior polar congenital cataract in a four-generation Chinese pedigree. The same mutation in this gene had previously been reported to be associated with other phenotype cataracts. This study is the first report relating a mutation of CRYBA1/A3 to posterior polar cataract.