A Novel Mutation in the CRYBA1 Gene is Associated with Autosomal Dominant Lamellar Cataract

Abstract

Abstract: : Purpose: To identify the gene responsible for autosomal dominant lamellar cataract in a four generation British family. Methods: 19 members of a family (13 affected, 3 unaffected and 3 married-in members) with inherited lamellar cataract agreed to take part in the study. Local ethical committee approval was granted and informed consent was obtained from all participants. A full clincal examination was performed, pedigree data collated, and leukocyte DNA extracted from venous blood for subsequent molecular genetic analysis. Linkage analysis by PCR-based microsatellite marker genotyping was used to identify the disease locus. Results: Ten affected members had had previous cataract surgery to one or both eyes and all unoperated eyes showed lamellar cataracts of variable severity. 33% (8 out of 24 eyes: one patient could not be examined) achieved visual acuities of 20/40. Significantly positive two-point lod scores were obtained for the markers D17S1857 (Z_max=3.32 at θ=0) and D17S1824 (Z_max=3.09 at θ=0) on 17q11. Screening of the CRYBA1 gene in this genetic region identified a 3 base pair deletion mutation that co-segregated with affected members in this family. This change is predicted to result in the deletion of an amino acid (G91del) within a highly conserved region of the protein. This sequence change was not found when 96 normal controls were screened. Conclusions: The lamellar cataract described in this family represents the third distinct phenotype to be associated with a CRYBA1 mutation. The loss of a glycine residue within the tyrosine corner of the second Greek key motif is likely to disrupt the domain structure of the protein and this study suggests that domain structure is important in the stabilization of the CRYBA1 protein during lens development.

Keywords: cataract • genetics • crystallins