Pathogenic mechanism of congenital cataract caused by the CRYBA1/A3-G91del variant and related intervention strategies.
Pathogenic mechanism of congenital cataract caused by the CRYBA1/A3-G91del variant and related intervention strategies.
复制标题
CRYBA1/A3-G91del变异引起先天性白内障的发病机制及相关干预策略。
DOI：
10.1016/j.ijbiomac.2021.08.111
复制
发表时间：
2021-08
影响因子：
8.2
通讯作者：
Chen Xiangjun
中科院分区：
文献类型：
--
作者：
Xu Jingjie;Wang Huaxia;Wu Chengpeng;Wang Ailing;Wu Wei;Xu Jia;Luo Chenqi;Ni Shuang;Yao Ke;Chen Xiangjun
先天性白内障是一种遗传异质性眼部疾病，在儿童时期会导致视力障碍。在我们以前的研究中，我们发现了一个新的突变，在外显子4的BA 1/BA 3基因，这导致了一个高度保守的甘氨酸在密码子91（G91 del）的缺失和核周悬韧带性白内障。G91 del变异是BA 1/BA 3中最常见的致病性突变之一，但其致病机制尚不清楚。在本研究中，我们纯化了βA3-晶体蛋白和βA3-G91 del变体。βA3-G91 del易被蛋白水解，溶解性和结构稳定性都很低。其次，我们构建了aerobic BA 1/BA 3突变体细胞模型，观察到G91 del突变体蛋白对环境胁迫更敏感，更容易形成聚集体。分子排阻色谱和分子动力学模拟结果表明，G91 del突变使βA3形成同源寡聚体的能力降低。此外，βA3-G91 del蛋白折叠过程复杂，呈现较多的中间状态，导致淀粉样纤维聚集，诱导细胞凋亡。最后，我们研究了由ABA 1/A3-G91 del变异体引起的先天性白内障的干预策略。羊毛甾醇的添加逆转了G91 del突变在外部压力下的负面影响。这项研究可能有助于探索相关白内障的潜在治疗策略。
Congenital cataracts, which are genetically heterogeneous eye disorders, lead to visual impairment in childhood. In our previous study, we identified a novel mutation in exon 4 of theCRYBA1/BA3gene, which resulted in the deletion of a highly conserved glycine at codon 91 (G91del) and perinuclear zonular cataract. The G91del variant is one of the most frequent pathogenic mutations inCRYBA1/BA3; however, its pathogenic mechanism remains unclear. In this study, we purified βA3-crystallin and the βA3-G91del variant. βA3-G91del was prone to proteolysis and exhibited very low solubility and low structural stability. Next, we constructed aCRYBA1/BA3mutant cell model and observed that G91del mutant proteins were more sensitive to environmental stress and prone to form aggregates. Size-exclusion chromatography and molecular dynamics simulation showed that the G91del mutation impaired the ability of βA3 to form homo-oligomers. In addition, the protein folding process of βA3-G91del was complicated and showed more intermediate states, resulting in amyloid fiber aggregation and induction of cellular apoptosis. Finally, we investigated intervention strategies for congenital cataract caused by the CRYBA1/A3-G91del variant. The addition of lanosterol reversed the negative effects of the G91del mutation under external stress. This study may help explore potential treatment strategies for related cataracts.