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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
Author(s) -
Wang Kai Jie,
Wang Sha,
Cao NiQian,
Yan YongBin,
Zhu Si Quan
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21436
Subject(s) - crystallin , biology , genetics , exon , mutation , gene , transversion , phenotype , microbiology and biotechnology
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 [θ]=0.0), which closely flanks the â‐crystallin gene cluster locus. Direct sequencing of the candidate âB1‐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 β‐crystallins revealed that the mutation impaired the structures of both βB1‐crystallin homomer and βB1/βA3‐crystallin heteromer. More importantly, the mutation significantly decreased the thermal stability of βB1/βA3‐crystallin but not βB1‐crystallin. These findings highlight the importance of protein‐protein interactions among β‐crystallins in maintaining lens transparency, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCMC. © 2011 Wiley‐Liss, Inc.