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Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

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
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:
DateEvent
1 March 2020Published
29 October 2019Published Online
25 October 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
SP/12/12/29836British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MR/K020919/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
204809/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
UNSPECIFIEDDinosaur TrustUNSPECIFIED
UNSPECIFIEDGreat Ormond Street Hospital Charityhttp://dx.doi.org/10.13039/501100001279
UNSPECIFIEDAssistance Publique Hôpitaux de Parishttp://dx.doi.org/10.13039/501100002738
UNSPECIFIEDInsermUNSPECIFIED
UNSPECIFIEDUniversité Paris-SudUNSPECIFIED
UNSPECIFIEDAgence Nationale de la Recherchehttp://dx.doi.org/10.13039/501100001665
RG/08/006/25302British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/13/4/30107British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/15/62/323032British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/15/59/31839British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/13/48/30453British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/18/52/33808British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 31661308
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111394
Publisher's version: https://doi.org/10.1164/rccm.201906-1141OC

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