A Novel Mutation in CRYBB1 Associated with Congenital Cataract-Microcornea Syndrome: The p. Ser129Arg Mutation Destabilizes the βB1/βA3-crystallin Heteromer But Not the βB1-crystallin Homomer

Congenital cataract-microcornea syndrome (CCMC) is a clinically and genetically heterogeneous condition characterized by lens opacities and microcornea. It appears as a distinct phenotype of heritable congenital cataract. Here we report a large Chinese family with autosomal dominant congenital cataract and microcornea. Evidence for linkage was detected at marker D22S1167 (LOD score [Z]=4.49, recombination fraction [theta]=0.0), which closely flanks the beta-crystallin gene cluster locus. Direct sequencing of the candidate beta B1-crystallin gene (CRYBB1) revealed a c.387C > A transversion in exon 4, which cosegregated with the disease in the family and resulted in the substitution of serine by arginine at codon 129 (p.Ser129Arg). A comparison of the biophysical properties of the recombinant beta-crystallins revealed that the mutation impaired the structures of both beta B1-crystallin homomer and beta B1/beta A3-crystallin heteromer. More importantly, the mutation significantly decreased the thermal stability of beta B1/beta A3-crystallin but not beta B1-crystallin. These findings highlight the importance of protein-protein interactions among beta-crystallins in maintaining lens transparency, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCMC. (C) 2010 Wiley-Liss, Inc.