A nonsense mutation (W9X) in CRYAA causes autosomal recessive cataract in an inbred Jewish Persian family

PURPOSE. TO identify the generic defect causing autosomal recessive catarac t in two inbred families. METHODS. Linkage analysis was performed with polymorphic markers close to 1 4 loci previously shown to be involved in autosomal dominant congenital cat aract. In one of the families a gene segregating with the disease was analy zed by single-strand conformation polymorphism (SSCP) and eventually sequen ced. RESULTS. Three polymorphic markers close to the CRYAA gene located on chrom osome 21q segregated with the disease phenotype in one of the families, but not in the other. Sequencing of the CRYAA in this Jewish Persian family re vealed a G-to-A substitution, resulting in the formation of a premature sto p codon (W9X). CONCLUSIONS. A nonsense mutation in the CRYAA gene causes autosomal recessi ve cataract in one family. This constitutes the first description of the mo lecular defect underlying nonsyndromic autosomal recessive congenital catar act. That there was no linkage to this locus in another family provides evi dence for genetic heterogeneity.