A Novel Mutation Impairing the Tertiary Structure and Stability of γC-Crystallin (CRYGC) Leads to Cataract Formation in Humans and Zebrafish Lens
A Novel Mutation Impairing the Tertiary Structure and Stability of γC-Crystallin (CRYGC) Leads to Cataract Formation in Humans and Zebrafish Lens
复制标题
DOI：
10.1002/humu.21648
复制
发表时间：
2012-02-01
期刊：
影响因子：
3.9
通讯作者：
Ma, Xu
中科院分区：
文献类型：
--
作者：
Li, Xiao-Qiao;Cai, Hong-Chen;Ma, Xu
先天性白内障是导致人类失明的主要原因之一。在这项研究中，我们确定了一个新的，杂合的c.385G>T突变，导致高度保守的甘氨酸取代密码子129（p.Gly129Cys）在中国三代常染色体显性遗传性先天性核性白内障的候选基因测序。以斑马鱼为模型，研究了γ C-晶状体蛋白p.Gly129Cys突变体引起的透镜空泡和不完全去核，重现了人类白内障的表型。分子模拟和光谱研究表明，该突变损害了蛋白质的三级结构，通过修改在C-末端结构域的氢键网络。该突变导致γ C-晶状体蛋白的热稳定性急剧下降，并且当在高浓度、热和UV照射应力下储存时聚集倾向显著增加。综上所述，这些结果表明，一种新的γ C-晶体蛋白p.Gly129Cys突变损害了蛋白质的三级结构，并导致白内障形成，这为突变如何影响γ C-晶体蛋白的结构，稳定性和功能提供了新的见解。我们的研究还强调了斑马鱼作为研究先天性遗传性白内障的有价值的模型工具。Mutat 33：391-401，2012. (C)2011 Wiley Periodicals，Inc.
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 gamma C-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 gamma C-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 gamma C-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 gamma C-crystallin structure, stability, and function. Our study also highlighted zebrafish as a valuable model tool for studying congenital inherited cataract. Hum Mutat 33:391-401, 2012. (C) 2011 Wiley Periodicals, Inc.