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
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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