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This study reveals <jats:italic>Periaxin (Prx)<\/jats:italic> 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-<jats:italic>Prx<\/jats:italic> variant synergistically disrupt fiber cell homeostasis and promote membrane\/F-actin aggregation, leading to severe age-related cataracts.<\/jats:p>","DOI":"10.1038\/s42003-025-08722-4","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T16:25:10Z","timestamp":1758731110000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Periaxin gene variants are linked to age-related cataracts in Cx46 deficient lenses"],"prefix":"10.1038","volume":"8","author":[{"given":"Chun-hong","family":"Xia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-915X","authenticated-orcid":false,"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-7290","authenticated-orcid":false,"given":"Bo","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2074-1802","authenticated-orcid":false,"given":"Xiaohua","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"8722_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fopht.2024.1362350","volume":"4","author":"H Choquet","year":"2024","unstructured":"Choquet, H. et al. 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