title: 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.
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.
authors.affiliation: Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, China.
authors.forename: Kai Jie
authors.initials: KJ
authors.lastname: Wang
authors.forename: Sha
authors.initials: S
authors.lastname: Wang
authors.forename: Ni-Qian
authors.initials: NQ
authors.lastname: Cao
authors.forename: Yong-Bin
authors.initials: YB
authors.lastname: Yan
authors.forename: Si Quan
authors.initials: SQ
authors.lastname: Zhu
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001483:Base Sequence; D002386:Cataract / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D003316:Corneal Diseases / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D008040:Genetic Linkage; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology; D020125:Mutation, Missense; D055503:Protein Multimerization; D055550:Protein Stability; D017422:Sequence Analysis, DNA; D038205:beta-Crystallin A Chain / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D038206:beta-Crystallin B Chain / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: C489108:CRYBA1 protein, human; C105601:CRYBB1 protein, human; D038205:beta-Crystallin A Chain; D038206:beta-Crystallin B Chain