A juvenile-onset, progressive cataract locus on chromosome 3q21-q22 is associated with a missense mutation in the beaded filament structural protein-2

Juvenile-onset cataracts are distinguished from congenital cataracts by the initial clarity of the lens at birth and the gradual development of lens o pacity in the second and third decades of life. Genomewide linkage analysis in a multigenerational pedigree, segregating for autosomal dominant juveni le-onset cataracts, identified a locus in chromosome region 3q21.2-q22.3. B ecause of the proximity of the gene coding for lens beaded filament structu ral protein-2 (BFSP2) to this locus, we screened for mutations in the codin g sequence of BFSP2. We observed a unique C-->T transition, one that was no t observed in 200 normal chromosomes. We predicted that this led to a nonco nservative R287W substitution in exon 4 that cosegregated with cataracts. T his mutation alters an evolutionarily conserved arginine residue in the cen tral rod domain of the intermediate filament. On consideration of the propo sed function of BFSP2 in the lens cytoskeleton, it is likely that this alte ration is the cause of cataracts in the members of the family we studied. T his is the first example of a mutation in a noncrystallin structural gene t hat leads to a juvenile-onset, progressive cataract.