A 5-base insertion in the gamma C-crystallin gene is associated with autosomal dominant variable zonular pulverulent cataract

A seven-generation family with 30 members affected by highly variable autos omal dominant zonular pulverulent cataracts has been previously described. We have localized the cataracts to a 19-cM interval on chromosome 2q33-q35 including the gamma-crystallin gene cluster. Maximum rod scores are 4.56 (t heta=0.02) with D2S157, 3.66 (theta=0.12) with D2572, and 3.57 (theta=0.052 ) with CRYG. Sequencing and allele-specific oligonucleotide analysis of the pseudo gamma E-crystallin promoter region from individuals in the pedigree suggest that activation of the gamma E-crystallin pseudo gene is unlikely to cause the cataracts in the family. In addition, base changes in the TATA box but not the Spl-binding site have been found in unaffected controls an d can be excluded as a sole cause of cataracts. In order to investigate the underlying genetic mechanism of cataracts in this family further, exons of the highly expressed gamma C- and gamma D-crystallin genes have been seque nced. The gamma D-crystallin gene shows no abnormalities, but a 5-bp duplic ation within exon 2 of the gamma C-crystallin gene has been found in one al lele of each affected family member and is absent from both unaffected fami ly members and unaffected controls. This mutation disrupts the reading fram e of the gamma C-crystallin coding sequence and is pre-dieted to result in the synthesis of an unstable gamma C-crystallin with 38 amino acids of the first "Greek key" motif followed by 52 random amino acids. This finding sug gests that the appropriate association of mutant beta gamma-crystallins int o oligomers is not necessary to cause cataracts and may give us new insight s into the genetic mechanism of cataract formation.