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Alpha-crystallin A chain (Heat shock protein beta-4) (HspB4) [Contains: Alpha-crystallin A(1-172); Alpha-crystallin A(1-168); Alpha-crystallin A(1-162)] [CRYA1] [HSPB4]


Polymorphism rs7278468 is associated with Age-related cataract through decreasing transcriptional activity of the CRYAA promoter.

CRYAA plays critical functional roles in lens transparency and opacity, and polymorphisms near CRYAA have been associated with age-related cataract (ARC). This study examines polymorphisms in the CRYAA promoter region for association with ARC and elucidates the mechanisms of this association. Three SNPs nominally associated with ARC were identified in the promoter region of CRYAA: rs3761382 (P = 0.06, OR (Odds ratio) = 1.5), rs13053109 (P = 0.04, OR = 1.6), rs7278468 (P = 0.007, OR = 0.6). The C-G-T haplotype increased the risk for ARC overall (P = 0.005, OR = 1.8), and both alleles and haplotypes show a stronger association with cortical cataract (rs3761382, P = 0.002, OR = 2.1; rs13053109, P = 0.002, OR = 2.1; rs7278468, P = 0.0007, OR = 0.5; C-G-T haplotype, P = 0.0003, OR = 2.2). The C-G-T risk haplotype decreased transcriptional activity through rs7278468, which lies in a consensus binding site for the transcription repressor KLF10. KLF10 binding inhibited CRYAA transcription, and both binding and inhibition were greater with the T rs7278468 allele. Knockdown of KLF10 in HLE cells partially rescued the transcriptional activity of CRYAA with rs7278468 T allele, but did not affect activity with the G allele. Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Aging
  • Alleles
  • Binding Sites
  • Case-Control Studies
  • Cataract
  • Cell Line
  • Crystallins
  • Early Growth Response Transcription Factors
  • Female
  • Genotype
  • Haplotypes
  • Humans
  • Kruppel-Like Transcription Factors
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering
  • Transcription, Genetic

A novel mutation (F71L) in alphaA-crystallin with defective chaperone-like function associated with age-related cataract.

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 (alphaA-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-alphaA-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 alphaA-crystallin. While the mutant alphaA-crystallin displayed significant (35-90%) loss of chaperone-like activity (CLA) in thermal aggregation of carbonic anhydrase, betaL- 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 alphaA-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.

MeSH Terms

  • Aging
  • Amino Acid Substitution
  • Base Sequence
  • Case-Control Studies
  • Cataract
  • Chromatography, Gel
  • Circular Dichroism
  • DNA Mutational Analysis
  • Electrophoresis, Polyacrylamide Gel
  • Exons
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Light
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutant Proteins
  • Mutation
  • Protein Structure, Quaternary
  • Scattering, Radiation
  • Spectrometry, Fluorescence
  • Time Factors
  • Tryptophan
  • alpha-Crystallin A Chain