Purpose: To identify the genetic defect causing autosomal recessive cataract in two inbred families.
Methods: Linkage analysis was performed with polymorphic markers close to 14 loci previously shown to be involved in autosomal dominant congenital cataract. In one of the families a gene segregating with the disease was analyzed by single-strand conformation polymorphism (SSCP) and eventually sequenced.
Results: Three polymorphic markers close to the CRYAA gene located on chromosome 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 revealed a G-to-A substitution, resulting in the formation of a premature stop codon (W9X).
Conclusions: A nonsense mutation in the CRYAA gene causes autosomal recessive cataract in one family. This constitutes the first description of the molecular defect underlying nonsyndromic autosomal recessive congenital cataract. That there was no linkage to this locus in another family provides evidence for genetic heterogeneity.