Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
AI Summary:
The study aimed to identify the molecular mechanisms underlying vascular Ehlers-Danlos syndrome (vEDS). The researchers found that vEDS is caused by mutations in the COL3A1 gene, which lead to misfolded collagen III protein. This misfolded protein causes ER stress and reduces cell proliferation and apoptosis.AI Topics:
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.
Omar, Ramla
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listLee, Michelle A.W.
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listGonzalez-Trueba, Laura
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listThomson, Cameron R.
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listHansen, Uwe
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listLianos, Spyridonas
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listHazarika, Snoopy
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listEl Abdallah, Omar
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listAmmar, Malak A.
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listCassels, Jennifer
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723
Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924
See full publications listMichie, Alison M.
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
Patterson, Shaun D. and Massett, Matthew E. and Huang, Xu and Jørgensen, Heather G. and Michie, Alison M. (2024) The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Molecular Oncology, 18 (9). pp. 2234-2254. ISSN 1574-7891
Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723
See full publications listBulleid, Neil J.
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listMalfait, Fransiska
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listVan Agtmael, Tom
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
See full publications listAvailable under License Creative Commons Attribution.
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