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

Autor:	Rao Y; Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China., Dong S; Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China., Li Z; Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China., Yang G; Department of Medical Genetics, School of Basic Medical Science, Wuhan University, Wuhan, China., Peng C; Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China., Yan M; Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, China., Zheng F; Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China.
Jazyk:	angličtina
Zdroj:	Molecular vision [Mol Vis] 2017 Sep 01; Vol. 23, pp. 624-637. Date of Electronic Publication: 2017 Sep 01 (Print Publication: 2017).
Abstrakt:	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 βB1-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 βB1-crystallin was significantly decreased, and the mutation diminished the chaperoning ability of αA-crystallin with the mutant under heating stress. Conclusions: Our findings highlight the importance of the C-terminus in βB1-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.
Databáze:	MEDLINE
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