A novel truncation mutation in CRYBB1 associated with autosomal dominant congenital cataract with nystagmus

作者：Rao, Yan; Dong, Sufang; Li, Zuhua; Yang, Guohua; Peng, Chunyan; Yan, Ming; Zheng, Fang^*

来源：Molecular Vision, 2017, 23: 624-637.

• CRYSTALLIN GENE-MUTATIONS
• ALPHA-A-CRYSTALLIN
• NONSENSE MUTATION
• CHINESE FAMILY
• NUCLEAR CATARACTS
• HUMAN LENS
• PULVERULENT CATARACT
• OPTICAL-QUALITY
• MICROCORNEA
• CRYAA

Purpose: To identify the potential candidate genes for a large Chinese family with autosomal dominant congenital cataract (ADCC) and nystagmus, and investigate the possible molecular mechanism underlying the role of the candidate genes in cataractogenesis.
Methods: We combined the linkage analysis and direct sequencing for the candidate genes in the linkage regions to identify the causative mutation. The molecular and bio-functional properties of the proteins encoded by the candidate genes was further explored with biophysical and biochemical studies of the recombinant wild-type and mutant proteins.
Results: We identified a c. C749T (p.Q227X) transversion in exon 6 of CRYBB1, a cataract-causative gene. This nonsense mutation changes a phylogenetically conserved glutamine to a stop codon and is predicted to truncate the C-terminus of the wild-type protein by 26 amino acids. Comparison of the biophysical and biochemical properties of the recombinant full-length and truncated beta B1-crystallins revealed that the mutation led to the insolubility and the phase separation phenomenon of the truncated protein with a changed conformation. Meanwhile, the thermal stability of the truncated beta B1-crystallin was significantly decreased, and the mutation diminished the chaperoning ability of alpha A-crystallin with the mutant under heating stress.
Conclusions: Our findings highlight the importance of the C-terminus in beta B1-crystallin in maintaining the crystalline function and stability, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human autosomal dominant congenital cataract.

• 出版日期2017-9
• 单位武汉大学