Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension

Joshua Hodgson, Emilia M. Swietlik, Richard M. Salmon, Charaka Hadinnapola, Ivana Nikolic, John Wharton, Jingxu Guo, James Liley, Matthias Haimel, Marta Bleda, Laura Southgate, Rajiv D. MacHado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Harm J. BogaardColin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Allan Lawrie, Robert V.Mac Kenzie Ross, Shahin Moledina, David Montani, Andrea Olschewski, Horst Olschewski, Willem H. Ouwehand, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Richard C. Trembath, Anton Vonk Noordegraaf, Stephen J. Wort, Martin R. Wilkins, Paul B. Yu, Wei Li, Stefan Gräf, Paul D. Upton, Nicholas W. Morrell

Research output: Contribution to journalArticlepeer-review


Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260). Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAHfemales. A subset of patients with PAHhadmarkedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9lossof functionandare likely causal.Thesemutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

Original languageEnglish
Pages (from-to)575-585
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number5
Publication statusPublished - Mar 1 2020


  • BMP10
  • BMP9
  • GDF2
  • Pulmonary arterial hypertension

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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