title: A novel mutation impairing the tertiary structure and stability of γC-crystallin (CRYGC) leads to cataract formation in humans and zebrafish lens.
abstract: Congenital cataract is one of the leading causes of human blindness. In this study, we identified a novel, heterozygous c.385G<T mutation in CRYGC that resulted in the substitution of a highly conserved glycine by cysteine at codon 129 (p.Gly129Cys) in a three-generation Chinese family with autosomal dominant congenital nuclear cataract by sequencing candidate genes. Using zebrafish as a model, we demonstrated that γC-crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H-bonding network in the C-terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC-crystallin, and a significant increase in the propensity of aggregation when subject to storage at high concentrations, heat, and UV- irradiation stresses. Taken together, these results indicate that a novel γC-crystallin p.Gly129Cys mutation impaired the tertiary structure of the protein and caused cataract formation, which provides a new insight into how the mutation may affect the γC-crystallin structure, stability, and function. Our study also highlighted zebrafish as a valuable model tool for studying congenital inherited cataract.
authors: Graduate School of Peking Union Medical College, Beijing, China.
authors: Xiao-Qiao
authors: XQ
authors: Li
authors: Hong-Chen
authors: HC
authors: Cai
authors: Shi-Yi
authors: SY
authors: Zhou
authors: Ju-Hua
authors: JH
authors: Yang
authors: Yi-Bo
authors: YB
authors: Xi
authors: Xiao-Bo
authors: XB
authors: Gao
authors: Wei-Jie
authors: WJ
authors: Zhao
authors: Peng
authors: P
authors: Li
authors: Guang-Yu
authors: GY
authors: Zhao
authors: Yi
authors: Y
authors: Tong
authors: Fan-Chen
authors: FC
authors: Bao
authors: Yan
authors: Y
authors: Ma
authors: Sha
authors: S
authors: Wang
authors: Yong-Bin
authors: YB
authors: Yan
authors: Cai-Ling
authors: CL
authors: Lu
authors: Xu
authors: X
authors: Ma
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002386:Cataract / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D055550:Protein Stability; D017434:Protein Structure, Tertiary / Q000235:genetics; D016415:Sequence Alignment; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D038222:gamma-Crystallins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D038222:gamma-Crystallins