Cataract mutation P20S of αB-crystallin impairs chaperone activity of αA-crystallin and induces apoptosis of human lens epithelial cells

Cataract is a common cause of childhood blindness worldwide. α-crystallin, which is comprised of two homologous subunits, αA- and αB-crystallin, plays a key role in the maintenance of lens transparency. Recently, we have identified a missense mutation in αB-crystallin that changes the proline residue at codon 20 to a serine residue (P20S) in a large Chinese family with autosomal dominant posterior polar congenital cataract. To explore the molecular mechanism by which the P20S mutation causes cataract, we examined the quaternary structure, subunit exchange and chaperone activity of the reconstituted heteroaggregates of α-crystallins containing wild type (WT) αA in combination with either WT-αB- or mutant αB-crystallin, respectively. Compared with heteroaggregates of WT-αA and WT-αB, heteroaggregates containing WT-αA and mutant αB showed nearly the same molecular mass, but the subunit-exchange rate and chaperone activity were decreased markedly. In human lens epithelial cells, unlike WT-αB-crystallin, the P20S mutant protein showed abnormal nuclear localization, and unusual ability to trigger apoptosis. These results suggest that the changes in the structure and function of the α-crystallin complex and cytotoxicity are vital factors in the pathogenesis of congenital cataract linked to the P20S mutation in the αB-crystallin.