ArticleAmerican journal of physiology. Lung cellular and molecular physiology2012
Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension.
Article in American journal of physiology. Lung cellular and molecular physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- A systematic review of genetic mutations in pulmonary arterial hypertension.BMC medical genetics · 2017Pooled it
- Thrombospondin-1 inhibits alternative complement pathway activation in antineutrophil cytoplasmic antibody-associated vasculitis.The Journal of clinical investigation · 2025Article
- Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology.International journal of molecular sciences · 2024Review
- Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts.Antioxidants (Basel, Switzerland) · 2023Article
- Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension.American journal of respiratory and critical care medicine · 2022Article
- Microvascular significance of TGF-β axis activation in COVID-19.Frontiers in cardiovascular medicine · 2022Review
- Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis.BMC cardiovascular disorders · 2021Article
- The renin-angiotensin system in COVID-19: Why ACE2 targeting by coronaviruses produces higher mortality in elderly hypertensive patients?BioEssays : news and reviews in molecular, cellular and developmental biology · 2021Review
- 'There and Back Again'-Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension.Genes · 2020Review
- THBS1 (thrombospondin-1).Atlas of genetics and cytogenetics in oncology and haematology · 2020Article
- Upregulated OCT3 has the potential to improve the survival of colorectal cancer patients treated with (m)FOLFOX6 adjuvant chemotherapy.International journal of colorectal disease · 2019Article
- Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease.Journal of scleroderma and related disorders · 2018Article
- A Review of Transcriptome Analysis in Pulmonary Vascular Diseases.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Genetics of Pulmonary Arterial Hypertension.Seminars in respiratory and critical care medicine · 2017Review
- Matricellular protein thrombospondin-1 in pulmonary hypertension: multiple pathways to disease.Cardiovascular research · 2017Review
- TheFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.Nature communications · 2017Article
- TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.Cardiovascular research · 2017Article
- Putting skin in the game: dermis-derived stem cells provide insight into familial pulmonary hypertension.Stem cell investigation · 2017Article
- EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension.Respiratory research · 2016Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene (BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-β and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene (THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-β regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-β. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted.
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