The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome.

ABSTRACT: Vascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to identify the molecular insults of mutations, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach. Analysis of two novel COL3A1 glycine mutations, G189S and G906R, in primary patient fibroblast cultures revealed secretion of misfolded collagen III and intracellular collagen retention leading to lower extracellular collagen levels. This was associated with matrix defects, endoplasmic reticulum (ER) stress, reduced cell proliferation and apoptosis. The ER stress was mediated by activation of IRE1 and PERK signalling arms with eviden

SUBMITTER: Omar R 

PROVIDER: S-EPMC12032211 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature