Reddy, M.A. and Bateman, O.A. and Chakarova, C. and Ferris, J. and Berry, V. and Lomas, E. and Sarra, R. and Smith, M.A. and Moore, A.T. and Bhattacharya, S.S. and Slingsby, Christine (2004) Characterization of the G91del CRYBA1/3-crystallin protein: a cause of human inherited cataract. Human Molecular Genetics 13 (9), pp. 945-953. ISSN 0964-6906.
Abstract
Congenital cataract is a leading cause of visual disability in children. Inherited isolated (non-syndromic) cataract represents a significant proportion of cases and the identification of genes responsible for inherited cataract will lead to a better understanding of the mechanism of cataract formation at the molecular level both in congenital and age-related cataract. Crystallins are abundantly expressed in the developing human lens and represent excellent candidate genes for inherited cataract. A genome-wide search of a five-generation family with autosomal dominant lamellar cataract demonstrated linkage to the 17p12–q11 region. Screening of the CRYBA1/3 gene showed a 3 bp deletion, which resulted in a G91del mutation within the tyrosine corner, that co-segregated with disease and was not found in 96 normal controls. In order to understand the molecular basis of cataract formation, the mutant protein was expressed in vitro and its unfolding and refolding characteristics assessed using far-UV circular dichroism spectroscopy. Defective folding and a reduction in solubility were found. As the wild-type protein did not refold into the native conformation following unfolding, a corresponding CRYBB2 mutant was genetically engineered and its refolding characteristics analysed and compared with wild-type CRYBB2. Its biophysical properties support the hypothesis that removal of the glycine residue from the tyrosine corner impairs the folding and solubility of β-crystallin proteins. This study represents the first comprehensive description of the biophysical consequences of a mutant β-crystallin protein that is associated with human inherited cataract.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Depositing User: | Sarah Hall |
| Date Deposited: | 21 May 2019 11:53 |
| Last Modified: | 02 Aug 2023 17:51 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/27612 |
Statistics
Additional statistics are available via IRStats2.
Archive Staff Only (login required)
