Periaxin gene variants are linked to age-related cataracts in Cx46 deficient lenses

Genetic predisposition affects cataract severity and progression, but no specific genetic modifier has been identified to date. This study reveals Periaxin (Prx) gene variants that cause four amino acid substitutions in the cytoskeletal scaffold protein Periaxin (PRX) between C57BL/6J (B6) and 129S4 (129) mouse strains, modulating the severity of age-related cataracts in connexin 46 knockout (Cx46KO) mice. Expression of 129-PRX is significantly higher than B6-PRX in the lens. Additionally, 129-PRX is broadly distributed across lens fibers, accumulates at fiber cell tricellular vertices, and co-localizes with actin filaments at surface protrusions in inner fibers and cultured cells. Aberrant membrane/F-actin aggregates and irregular fibers appear only in the 129-Cx46KO lens core with severe nuclear cataracts. These findings suggest that Cx46 deficiency and the gain-of-function 129-Prx variant synergistically disrupt fiber cell homeostasis and promote membrane/F-actin aggregation, leading to severe age-related cataracts.