Hodgson, J;
Swietlik, EM;
Salmon, RM;
Hadinnapola, C;
Nikolic, I;
Wharton, J;
Guo, J;
Liley, J;
Haimel, M;
Bleda, M;
et al.
Hodgson, J; Swietlik, EM; Salmon, RM; Hadinnapola, C; Nikolic, I; Wharton, J; Guo, J; Liley, J; Haimel, M; Bleda, M; Southgate, L; Machado, RD; Martin, JM; Treacy, CM; Yates, K; Daugherty, LC; Shamardina, O; Whitehorn, D; Holden, S; Bogaard, HJ; Church, C; Coghlan, G; Condliffe, R; Corris, PA; Danesino, C; Eyries, M; Gall, H; Ghio, S; Ghofrani, H-A; Gibbs, JSR; Girerd, B; Houweling, AC; Howard, L; Humbert, M; Kiely, DG; Kovacs, G; Lawrie, A; MacKenzie Ross, RV; Moledina, S; Montani, D; Olschewski, A; Olschewski, H; Ouwehand, WH; Peacock, AJ; Pepke-Zaba, J; Prokopenko, I; Rhodes, CJ; Scelsi, L; Seeger, W; Soubrier, F; Suntharalingam, J; Toshner, MR; Trembath, RC; Vonk Noordegraaf, A; Wort, SJ; Wilkins, MR; Yu, PB; Li, W; Gräf, S; Upton, PD; Morrell, NW
(2020)
Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.
Am J Respir Crit Care Med, 201 (5).
pp. 575-585.
ISSN 1535-4970
https://doi.org/10.1164/rccm.201906-1141OC
SGUL Authors: Southgate, Laura
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Abstract
OBJECTIVES: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating bone morphogenetic protein, BMP9, which is a ligand for the BMP type 2 receptor (BMPR2). Here we determine the functional impact of GDF2 mutations and characterised 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 signalling and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in PAH patients with GDF2 mutations, and controls. Levels were also measured in a larger cohort of controls (n=120) and idiopathic PAH patients (n=260). MAIN RESULTS: We identified novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. PAH patients carrying 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 PAH patients and controls, BMP10 levels were lower in PAH females. A subset of PAH patients 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 signalling in PAH.
Item Type: |
Article
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Additional Information: |
Originally Published in: Hodgson, J; Swietlik, EM; Salmon, RM; Hadinnapola, C; Nikolic, I; Wharton, J; Guo, J; Liley, J; Haimel, M; Bleda, M; et al. (Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine 2019; 201:575:585.
DOI: 10.1164/rccm.201906-1141OC
Copyright © 2019 by the American Thoracic Society
The final publication is available at https://doi.org/10.1164/rccm.201906-1141OC. |
Keywords: |
BMP10, BMP9, GDF2, Pulmonary arterial hypertension, 11 Medical And Health Sciences, Respiratory System |
Journal or Publication Title: |
Am J Respir Crit Care Med |
ISSN: |
1535-4970 |
Language: |
eng |
Dates: |
Date | Event |
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1 March 2020 | Published | 29 October 2019 | Published Online | 25 October 2019 | Accepted |
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Publisher License: |
Publisher's own licence |
Projects: |
|
PubMed ID: |
31661308 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111394 |
Publisher's version: |
https://doi.org/10.1164/rccm.201906-1141OC |
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