Human Molecular Genetics Advance Access originally published online on March 11, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 9 945-953
DOI: 10.1093/hmg/ddh110
Human Molecular Genetics, Vol. 13, No. 9 © Oxford University Press 2004; all rights reserved
Characterization of the G91del CRYBA1/3-crystallin protein: a cause of human inherited cataract
1Department of Molecular Genetics, Institute of Ophthalmology, 11–43 Bath Street, London EC1V 9EL, UK, 2Department of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK, 3Department of Ophthalmology, Cheltenham General Hospital, Cheltenham, UK and 4Human Genome Mapping Project Resource Centre, Babraham, Cambridge, UK
Received January 5, 2004; Revised February 18, 2004; Accepted March 3, 2004
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 ß-crystallin proteins. This study represents the first comprehensive description of the biophysical consequences of a mutant ß-crystallin protein that is associated with human inherited cataract.
* To whom correspondence should be addressed. Tel: +44 12236086800; Fax: +44 2076086863; Email: mareddy{at}doctors.org.uk
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