ArticleMolecular genetics & genomic medicine2021
Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children.
Article in Molecular genetics & genomic medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 37 citations in OpenAlex.
- An Ancient Founder GDF2 Variant Potentially Causes Semi-Dominant Non-Syndromic Pulmonary Arterial Hypertension.Clinical genetics · 2026Article
- Pulmonary arterial hypertension induces a metabolic and inflammatory hepatopathy.The Journal of clinical investigation · 2026Article
- Molecular-Genetic Basis of Pulmonary Arterial Hypertension (PAH).Current issues in molecular biology · 2026Review
- Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations.Translational stroke research · 2026Review
- Pulmonary Arterial Hypertension Induces a Metabolic and Inflammatory Hepatopathy.bioRxiv : the preprint server for biology · 2026Article
- Cerebrovascular Malformations Associated With Hereditary Hemorrhagic Telangiectasia and HHT-Like Syndromes: A Comparative Overview.European journal of neurology · 2026Review
- BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity.Angiogenesis · 2025Article
- Bone morphogenetic protein 10 is increased in pre-capillary pulmonary hypertension patients.Cardiovascular research · 2025Article
- The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis.Journal of clinical medicine · 2025Review
- Clinical Phenotypes of a Pediatric Cohort withJournal of clinical medicine · 2025Article
- Extracranial arteriovenous malformations: towards etiology-based therapeutic management.The Journal of clinical investigation · 2025Review
- From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations.Angiogenesis · 2025Review
- Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.American journal of human genetics · 2024Article
- Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition.Biomedicines · 2024Review
- Effects of Modulating BMP9, BMPR2, and AQP1 on BMP Signaling in Human Pulmonary Microvascular Endothelial Cells.International journal of molecular sciences · 2024Article
- Bone morphogenetic protein signalling in pulmonary arterial hypertension: revisiting the BMPRII connection.Biochemical Society transactions · 2024Review
- Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease.Journal of cellular and molecular medicine · 2024Review
- Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.International journal of molecular sciences · 2024Article
- Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances.The Journal of clinical investigation · 2024Review
- Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
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Authors and funding
16 authors at 8 institutions in 3 countries.
Funding
Abstract
backgroundDisrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra-rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases.
methodsPlasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE-luciferase reporter cell line (HMEC1-BRE). Proteins were expressed for assessment of secretion and processing.
resultsPlasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum-derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9.
conclusionCollectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or "HHT-like" telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs.
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