A novel mutation (F71L) in alphaA-crystallin with defective chaperone-like function associated with age-related cataract.
A novel mutation (F71L) in alphaA-crystallin with defective chaperone-like function associated with age-related cataract.
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DOI：
10.1016/j.bbadis.2009.06.011
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发表时间：
2009-10
影响因子：
6.2
通讯作者：
Padma, T.
中科院分区：
文献类型：
--
作者：
Bhagyalaxmi, S. G.;Srinivas, P. N. B. S.;Barton, Kelly A.;Kumar, K. Ravi;Vidyavathi, M.;Petrash, J. Mark;Reddy, G. Bhanuprakash;Padma, T.
关键词：
Age-related cataract (ARC) is a multifactorial disease and the leading cause of visual impairment and blindness worldwide. Genetic predisposition in association with other etiological factors may contribute to ARC. Although, there is some evidence for genetic influence for development of ARC, reports on gene mutations associated with ARC are scanty. In the present work, we identified a genetic variation (F71L) in the exon-2 of CRYAA gene in three unrelated female sporadic cases among 450 ARC patients but not in 144 normal non-cataractous controls. By comparing human recombinant wild-type and F71L-αA-crystallin, further we characterized the functional significance of this missense mutation. Size exclusion chromatography studies revealed that F71L mutation had no significant effect on the apparent molecular mass of αA-crystallin oligomeric complex. Intrinsic tryptophan fluorescence and far- and near-UV CD spectra indicated that F71L missense mutation did not significantly affect the secondary and tertiary structures of αA-crystallin. The ANS fluorescence emission spectra suggested no changes in surface hydrophobicity due to the F71L substitution. While the mutant αA-crystallin displayed almost complete loss (90%) of chaperone-like activity (CLA), in thermal aggregation of carbonic anhydrase, it showed 35-50% less protection in heat-induced aggregation of βL- and γ-crystallins. This is the first report of an αA-F71L mutation being associated with ARC. The results are consistent with the hypothesis that the mechanism of 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.
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