Pathogenic mechanism of congenital cataract caused by the CRYBA1/A3-G91del variant and related intervention strategies.

Abstract

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 the CRYBA1/BA3 gene, 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 in CRYBA1/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 a CRYBA1/BA3 mutant 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.

• Authors: Jingjie Xu, Huaxia Wang, Chengpeng Wu, Ailing Wang, Wei Wu, Jia Xu, Chenqi Luo, Shuang Ni, Ke Yao, Xiangjun Chen
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 189 Pg. 44-52 (Oct 31 2021) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 34419537 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• CRYBA1 protein, human
• Mutant Proteins
• Protein Aggregates
• beta-Crystallin A Chain
• Lanosterol
• Guanidine

Topics

• Apoptosis (drug effects)
• Cataract (congenital, genetics)
• Cell Line
• Genetic Predisposition to Disease
• Guanidine (pharmacology)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Lanosterol (pharmacology)
• Mutant Proteins (chemistry, metabolism)
• Mutation (genetics)
• Protein Aggregates (drug effects)
• Protein Denaturation
• Temperature
• beta-Crystallin A Chain (chemistry, genetics, ultrastructure)