外周髓鞘蛋白基因变异与Cx46缺陷晶状体中的年龄相关性白内障有关。

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

作者信息

Xia Chun-Hong, Wang Eddie, Li Lin, Wang Dong, Chang Bo, Li Mei, Gong Xiaohua

机构信息

Vision Science and School of Optometry, University of California, Berkeley, Berkeley, CA, USA.

The Jackson Laboratory, Bar Harbor, ME, USA.

出版信息

Commun Biol. 2025 Sep 24;8(1):1356. doi: 10.1038/s42003-025-08722-4.

DOI:10.1038/s42003-025-08722-4

PMID:40993206

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12460658/

Abstract

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.

摘要

遗传易感性会影响白内障的严重程度和进展，但迄今为止尚未确定具体的遗传修饰因子。本研究揭示了在C57BL/6J（B6）和129S4（129）小鼠品系之间，导致细胞骨架支架蛋白外周蛋白（PRX）出现四个氨基酸替换的外周蛋白（Prx）基因变异，这些变异调节了连接蛋白46基因敲除（Cx46KO）小鼠年龄相关性白内障的严重程度。129-PRX在晶状体中的表达明显高于B6-PRX。此外，129-PRX广泛分布于晶状体纤维中，在纤维细胞的三细胞顶点积聚，并在内层纤维和培养细胞的表面突起处与肌动蛋白丝共定位。异常的膜/F-肌动蛋白聚集体和不规则纤维仅出现在具有严重核性白内障的129-Cx46KO晶状体核心中。这些发现表明，Cx46缺乏和功能获得性129-Prx变异协同破坏纤维细胞稳态并促进膜/F-肌动蛋白聚集，导致严重的年龄相关性白内障。