A novel mutation impairing the tertiary structure and stability of gammaC-crystallin leads to cataract formation in humans and zebrafish lens
- Authors
- Li, X.Q., Cai, H.C., Zhou, S.Y., Yang, J.H., Xi, Y.B., Gao, X.B., Zhao, W.J., Li, P., Zhao, G.Y., Tong, Y., Bao, F.C., Ma, Y., Wang, S., Yan, Y.B., Lu, C.L., and Ma, X.
- ID
- ZDB-PUB-111117-18
- Date
- 2012
- Source
- Human Mutation 33(2): 391-401 (Journal)
- Registered Authors
- Keywords
- cataract, γC-crystallin, mutation, zebrafish, protein stability
- MeSH Terms
-
- Amino Acid Sequence
- Amino Acid Substitution
- Animals
- Base Sequence
- Cataract/diagnosis
- Cataract/genetics*
- Cataract/metabolism
- Child
- Female
- Humans
- Male
- Models, Molecular
- Molecular Sequence Data
- Mutation*
- Pedigree
- Phenotype
- Protein Stability
- Protein Structure, Tertiary/genetics
- Sequence Alignment
- Zebrafish/genetics
- Zebrafish/metabolism
- gamma-Crystallins/chemistry*
- gamma-Crystallins/genetics*
- gamma-Crystallins/metabolism
- PubMed
- 22052681 Full text @ Hum. Mutat.
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.