Autosomal dominant zonular cataract with sutural opacities is associated with a splice mutation in the betaA3/A1-crystallin gene.

PURPOSE Congenital cataracts constitute a morphologically and genetically heterogeneous group of diseases that are a major cause of childhood blindness. Autosomal Dominant Zonular Cataracts with Sutural Opacities (CCZS) have been mapped to chromosome 17q11-q12 near the betaA3A1-crystallin gene (CRYBA1). The betaA3A1-crystallin gene was investigated as the causative gene for the cataracts. METHODS The betaA3/A1-crystallin gene was sequenced in affected and control individuals. Base changes were confirmed and assayed in additional family members and controls using NlaIII restriction digestion of PCR amplified DNA sequences. Base changes were assessed for their effects on splicing by information analysis. RESULTS The cataracts are associated with a sequence change in the 5' (donor) splice site of intron 3: GC(g->a)tgagt. The sequence change also creates a new NlaIII site. This base change cosegregates with the cataracts in this family, being present in every affected individual. Conversely, this base change was not seen in 140 chromosomes examined in 70 unaffected and unrelated individuals. Information theory mutational analysis shows that the base change lowers the information content of the splice site from 6.0 to -6.8 bits, so that splicing would not be expected to occur at the altered site. CONCLUSIONS Taken together, these observations suggest that the observed mutation might be causally related to the cataracts in this family.