Activation of the unfolded protein response by a cataract-associated αA-crystallin mutation

Gregory W. Watson, Usha P. Andley

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αA-crystallin is a lens chaperone that plays an essential role in the transparency and refractive properties of the lens. Mutations in αA-crystallin have been associated with the development of hereditary cataracts. The R49C mutation of αA-crystallin (αA-R49C) was identified in a four-generation Caucasian family with hereditary cataracts. The αA-R49C protein forms larger-than-normal oligomers in the lens and has decreased solubility. This aberrant αA-R49C oligomerization suggests that protein folding is altered. However, whether activation of the unfolded protein response (UPR) occurs during crystallin mutation-induced cataract formation and whether the UPR causes cell death under these conditions is unclear. We investigated UPR activation in an in vivo mouse model of αA-R49C using immunoblot analysis of lens extracts. We found that expression of the endoplasmic reticulum (ER) chaperone, BiP, was 5-fold higher in homozygous αA-R49C lenses than in wild type lenses. Analysis of proteins typically expressed during the UPR revealed that ATF-4 and CHOP levels were also higher in homozygous lenses than in wild type lenses, while the opposite was true of ATF-6 and XBP-1. Taken together, these findings show that mutation of αA-crystallin induces activation of the UPR during cataract formation. They also suggest that the UPR is an important mediator of cell death observed in homozygous αA-R49C lenses.

Original languageEnglish
Pages (from-to)192-196
Number of pages5
JournalBiochemical and Biophysical Research Communications
Issue number2
StatePublished - Oct 15 2010


  • Cataract
  • Crystallin
  • Lens
  • Mutation
  • Unfolded protein response


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