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The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome
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The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome
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Journal Article
The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome
2025
Overview
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 evidence of allelic heterogeneity. To establish if promoting ER protein folding capacity or protein degradation represents novel therapeutic avenues, we investigated the efficacy of FDA-approved small molecules. The chemical chaperone 4-phenylbutyric acid (PBA) rescued the ER stress and thermostability of secreted collagen leading to reduced apoptosis and matrix defects, and its efficacy was influenced by duration, dosage and allelic heterogeneity. Targeting protein degradation with carbamazepine (CBZ), or PBA-CBZ in combination did not increase treatment efficacy. These data establish that ER stress is a molecular mechanism in vEDS that can be influenced by the position of
COL3A1
mutation. It combines with matrix defects due to reduced collagen III levels and/or mutant protein secretion to vEDS pathogenesis. Targeting protein folding using FDA-approved chemical chaperones represents a putative mechanism-based therapeutic approach for vEDS that can rescue intra- and extracellular defects.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
