Characterization of the G91del CRYBA1/3-crystallin protein: a cause of human inherited cataract
| Autor: | R. Sarra, M.A. Smith, J. Ferris, O.A. Bateman, Vanita Berry, C. Slingsby, A. T. Moore, Shomi S. Bhattacharya, E. Lomas, M.A. Reddy, Christina Chakarova |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Candidate gene Protein Folding genetic structures Genetic Linkage Protein Conformation Mutant Molecular Sequence Data Glycine medicine.disease_cause Cataract beta-Crystallin A Chain Crystallin Mutant protein Genetics medicine Humans Amino Acid Sequence Tyrosine Molecular Biology Gene Genetics (clinical) Genes Dominant Sequence Deletion Mutation biology General Medicine Crystallins eye diseases Solubility biology.protein Female sense organs Protein A |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0964-6906 |
| Popis: | 9 páginas, 6 figuras, 2 tablas.-- et al. 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. The work at the Department of Molecular Genetics, Institute of Ophthalmology was supported by a Wellcome Trust grant 063969/Z/01. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|