Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1792, Issue 10, Pages 974-981Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2009.06.011
Keywords
Age-related cataract; alpha A-crystallin; F71L-mutation; SSCP; RFLP; Chaperone-like activity; CD spectra; Hydrophobicity
Funding
- NEI NIH HHS [R01 EY013897] Funding Source: Medline
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Age-related cataract (ARC) is a multifactorial disease and the leading cause of blindness worldwide. Genetic predisposition in association with other etiological factors may contribute to ARC. However, gene mutation studies on ARC are scanty. In the present work, we identified a genetic variation (F71L) in the exon-2 of CRYAA (alpha A-crystallin) gene in three unrelated female sporadic cases among 711 ARC patients but not in 265 normal non-cataractous controls by SSCP and RFLP analysis. By comparing human recombinant wild-type and F71L-alpha A-crystallin, we characterized the functional significance of this missense mutation. Chromatography, fluorescence and far- and near-UV CD studies indicated that F71L missense mutation did not significantly affect the apparent molecular mass, secondary and tertiary structures and hydrophobicity of alpha A-crystallin. While the mutant alpha A-crystallin displayed significant (35-90%) loss of chaperone-like activity (CLA) in thermal aggregation of carbonic anhydrase, beta L- and gamma-crystallins. it showed moderate (10-50%) loss in CLA in DTT-induced aggregation of insulin and lysozyme. This is the first report of an alpha A-F71L mutation being associated with ARC and suggests that ARC in individuals carrying this mutation (F71L) might be due to the overall loss of in vivo chaperone activity due to interaction with other environmental factors. (C) 2009 Elsevier B.V. All rights reserved
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