Abstract
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.
Highlights
Congenital cataract is a clinically and genetically heterogeneous group of eye disorders that accounts for onetenth of the cases of childhood blindness (Gilbert, et al, 1993)
In this study, we have identified a novel causative mutation p.Ser129Arg in CRYBB1 in a large Chinese family with cataract-microcornea syndrome (CCMC). βB1-crystallin is a major subunit of the β-crystallins and comprises 9% of the total soluble crystallin in the human lens (Lampi, et al, 1997)
The mutation detected in this family is located in exon 4, which encodes the Greek key II, and replaces the polar uncharged serine by the charged residue arginine at position 129
Summary
Congenital cataract is a clinically and genetically heterogeneous group of eye disorders that accounts for onetenth of the cases of childhood blindness (Gilbert, et al, 1993). Congenital cataract tends to be inherited in a Mendelian mode, and can be isolated or occur in association with other ocular or systemic diseases. Congenital cataract-microcornea syndrome (CCMC; MIM# 116150) appears as a distinct phenotype affecting 12%-18% of heritable congenital cataract cases (Hansen, et al, 2007), and characterized by lens opacity and a corneal diameter smaller than 11 mm (Easty, et al, 1999). The molecular mechanisms of CCMC caused by these gene mutations are still unclear. Functional analysis of mutant gene product is needed to disclose the underlying pathogenesis of CCMC
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