Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension
Autor: | Christopher J. Rhodes, Allan Lawrie, Robert V. MacKenzie Ross, Mark Toshner, Mélanie Eyries, Werner Seeger, Richard M. Salmon, Stefano Ghio, Laura Scelsi, Stephen J. Wort, Gabor Kovacs, Florent Soubrier, J. Simon R. Gibbs, Richard C. Trembath, Jennifer M. Martin, Nicholas W. Morrell, Matthias Haimel, Gerry Coghlan, Marc Humbert, Jay Suntharalingam, Charaka Hadinnapola, Cesare Danesino, Willem H. Ouwehand, Louise C. Daugherty, Carmen M. Treacy, David G. Kiely, Andrea Olschewski, Joanna Pepke-Zaba, Deborah Whitehorn, Anton Vonk Noordegraaf, Andrew J. Peacock, Robin Condliffe, Horst Olschewski, Paul A. Corris, Joshua Hodgson, Hossein Ardeschir Ghofrani, Arjan C. Houweling, Colin Church, Jingxu Guo, Stefan Gräf, Barbara Girerd, Katherine Yates, Harm Jan Bogaard, Ivana Nikolic, Luke S. Howard, Henning Gall, Laura Southgate, Olga Shamardina, Emilia M. Swietlik, Marta Bleda, Rajiv D. Machado, Inga Prokopenko, John Wharton, James Liley, Simon Holden, Paul B. Yu, Martin R. Wilkins, Shahin Moledina, David Montani, Paul D. Upton, Wei Li |
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Přispěvatelé: | Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Swietlik, Emilia [0000-0002-4095-8489], Guo, Jingxu [0000-0002-1568-4842], Shamardina, Olga [0000-0003-4994-2157], Ouwehand, Willem [0000-0002-7744-1790], Toshner, Mark [0000-0002-3969-6143], Li, Wei [0000-0002-1924-3120], Graf, Stefan [0000-0002-1315-8873], Upton, Paul [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, APH - Quality of Care, ACS - Atherosclerosis & ischemic syndromes, British Heart Foundation |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Pulmonary and Respiratory Medicine
Adult Male medicine.medical_specialty Heterozygote DNA Copy Number Variations [SDV]Life Sciences [q-bio] Respiratory System Mutation Missense GDF2 Critical Care and Intensive Care Medicine Bone morphogenetic protein BMP9 03 medical and health sciences 0302 clinical medicine Sex Factors Critical Care Medicine Sex factors Internal medicine General & Internal Medicine pulmonary arterial hypertension medicine Growth Differentiation Factor 2 Humans In patient 030212 general & internal medicine Respiratory system 11 Medical and Health Sciences Science & Technology business.industry Case-control study Heterozygote advantage Middle Aged 3. Good health Transport protein BMP10 Protein Transport Endocrinology 030228 respiratory system Case-Control Studies Bone Morphogenetic Proteins Female business Life Sciences & Biomedicine |
Zdroj: | American Journal of Respiratory and Critical Care Medicine American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2020, 201 (5), pp.575-585. ⟨10.1164/rccm.201906-1141OC⟩ Hodgson, J, Swietlik, E M, Salmon, R M, Hadinnapola, C, Nikolic, I, Wharton, J, Guo, J, Liley, J, Haimel, M, Bleda, M, Southgate, L, Machado, R D, Martin, J M, Treacy, C M, Yates, K, Daugherty, L C, Shamardina, O, Whitehorn, D, Holden, S, Bogaard, H J, Church, C, Coghlan, G, Condliffe, R, Corris, P A, Danesino, C, Eyries, M, Gall, H, Ghio, S, Ghofrani, H-A, Gibbs, J S R, Girerd, B, Houweling, A C, Howard, L, Humbert, M, Kiely, D G, Kovacs, G, Lawrie, A, MacKenzie Ross, R V, Moledina, S, Montani, D, Olschewski, A, Olschewski, H, Ouwehand, W H, Peacock, A J, Pepke-Zaba, J, Prokopenko, I, Rhodes, C J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M R, Trembath, R C, Vonk Noordegraaf, A, Wort, S J, Wilkins, M R, Yu, P B, Li, W, Gräf, S, Upton, P D & Morrell, N W 2020, ' Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension ', American Journal of Respiratory and Critical Care Medicine, vol. 201, no. 5, pp. 575-585 . https://doi.org/10.1164/rccm.201906-1141OC American Journal of Respiratory and Critical Care Medicine, 201(5), 575-585. American Thoracic Society |
ISSN: | 1073-449X 1535-4970 |
Popis: | International audience; 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 PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH. |
Databáze: | OpenAIRE |
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