ArticleHuman molecular genetics2019
4-Sodium phenyl butyric acid has both efficacy and counter-indicative effects in the treatment of Col4a1 disease.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
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- Alteplase and Angioedema: Can Clinical Exome Sequencing Redefine the Paradigm?Life (Basel, Switzerland) · 2026Article
- Collagen IV in Gould syndrome and Alport syndrome.Nature reviews. Nephrology · 2025Review
- A collagen IV fluorophore knock-in toolkit reveals trimer diversity in C. elegans basement membranes.The Journal of cell biology · 2025Article
- A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome.The Journal of cell biology · 2025Article
- The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome.Cell death discovery · 2025Article
- Collagen formation, function and role in kidney disease.Nature reviews. Nephrology · 2025Review
- Skeletal pathology in mouse models of Gould syndrome is partially alleviated by genetically reducing TGFβ signaling.Matrix biology : journal of the International Society for Matrix Biology · 2024Article
- Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage.EBioMedicine · 2024Article
- A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases.Stem cell reports · 2023Article
- Genetic Causes of Cerebral Small Vessel Diseases: A Practical Guide for Neurologists.Neurology · 2023Review
- Current and Future Therapeutical Options in Alport Syndrome.International journal of molecular sciences · 2023Review
- Elevated TGFβ signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome.Matrix biology : journal of the International Society for Matrix Biology · 2023Article
- Elevated TGFβ signaling contributes to ocular anterior segment dysgenesis in Col4a1 mutant mice.Matrix biology : journal of the International Society for Matrix Biology · 2022Article
- Novel Therapies for Alport Syndrome.Frontiers in medicine · 2022Review
- Development and validation of a nomogram to predict the 30-day mortality risk of patients with intracerebral hemorrhage.Frontiers in neuroscience · 2022Article
- Identification of an Altered Matrix Signature in Kidney Aging and Disease.Journal of the American Society of Nephrology : JASN · 2021Article
- Identification of fibronectin 1 as a candidate genetic modifier in a Col4a1 mutant mouse model of Gould syndrome.Disease models & mechanisms · 2021Article
- Targeting cellular stress in vitro improves osteoblast homeostasis, matrix collagen content and mineralization in two murine models of osteogenesis imperfecta.Matrix biology : journal of the International Society for Matrix Biology · 2021Article
- Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts.Biomaterials · 2020Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in the collagen genes COL4A1 and COL4A2 cause Mendelian eye, kidney and cerebrovascular disease including intracerebral haemorrhage (ICH), and common collagen IV variants are a risk factor for sporadic ICH. COL4A1 and COL4A2 mutations cause endoplasmic reticulum (ER) stress and basement membrane (BM) defects, and recent data suggest an association of ER stress with ICH due to a COL4A2 mutation. However, the potential of ER stress as a therapeutic target for the multi-systemic COL4A1 pathologies remains unclear. We performed a preventative oral treatment of Col4a1 mutant mice with the chemical chaperone phenyl butyric acid (PBA), which reduced adult ICH. Importantly, treatment of adult mice with the established disease also reduced ICH. However, PBA treatment did not alter eye and kidney defects, establishing tissue-specific outcomes of targeting Col4a1-derived ER stress, and therefore this treatment may not be applicable for patients with eye and renal disease. While PBA treatment reduced ER stress and increased collagen IV incorporation into BMs, the persistence of defects in BM structure and reduced ability of the BM to withstand mechanical stress indicate that PBA may be counter-indicative for pathologies caused by matrix defects. These data establish that treatment for COL4A1 disease requires a multipronged treatment approach that restores both ER homeostasis and matrix defects. Alleviating ER stress is a valid therapeutic target for preventing and treating established adult ICH, but collagen IV patients will require stratification based on their clinical presentation and mechanism of their mutations.
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