Progressive juvenile-onset punctate cataracts caused by mutation of the gamma D-crystallin gene

Cataracts are a significant public health problem. Here, we describe the ge netic alteration responsible far a progressive form of cataract, segregatin g as an autosomal dominant trait in a three-generation pedigree, Unlike mos t autosomal dominant cataracts, these are not clinically apparent at birth but are initially observed in the first year or two of life. The opacificat ion evolves relatively slowly, generally necessitating removal of the lens in childhood or early adolescence. A genome-wide search in our kindred reve aled linkage at 2q33-35 where the gamma-crystallin gene cluster resides. A single base alteration resulting in an Arg- 14 --> Cys (R14C) substitution in gamma D-crystallin was subsequently identified. Protein modeling suggest s that the effect of this mutation is a subtle one, affecting the surface p roperties of the crystallin molecule rather than its tertiary structure, co nsistent with the fact that the patients' lenses are normal at birth. This is the first gene defect shown to be responsible for a noncongenital progre ssive cataract, and studying the defective protein should teach us more abo ut the mechanisms underlying cataract formation.