Imperial College London
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DrChristopherRhodes

Faculty of Medicine, National Heart & Lung Institute

Reader in Pulmonary Vascular Disease
 
 
 
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Contact

 

+44 (0)20 7594 7638c.rhodes07

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hodgson:2020:10.1164/rccm.201906-1141OC,
author = {Hodgson, J and Swietlik, EM and Salmon, RM and Hadinnapola, C and Nikolic, I and Wharton, J and Guo, J and Liley, J and Haimel, M and Bleda, M and Southgate, L and Machado, RD and Martin, JM and Treacy, CM and Yates, K and Daugherty, LC and Shamardina, O and Whitehorn, D and Holden, S and Bogaard, HJ and Church, C and Coghlan, G and Condliffe, R and Corris, PA and Danesino, C and Eyries, M and Gall, H and Ghio, S and Ghofrani, H-A and Gibbs, JSR and Girerd, B and Houweling, AC and Howard, L and Humbert, M and Kiely, DG and Kovacs, G and Lawrie, A and MacKenzie, Ross RV and Moledina, S and Montani, D and Olschewski, A and Olschewski, H and Ouwehand, WH and Peacock, AJ and Pepke-Zaba, J and Prokopenko, I and Rhodes, CJ and Scelsi, L and Seeger, W and Soubrier, F and Suntharalingam, J and Toshner, MR and Trembath, RC and Vonk, Noordegraaf A and Wort, SJ and Wilkins, MR and Yu, PB and Li, W and Gräf, S and Upton, PD and Morrell, NW},
doi = {10.1164/rccm.201906-1141OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {575--585},
title = {Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension},
url = {http://dx.doi.org/10.1164/rccm.201906-1141OC},
volume = {201},
year = {2020}
}
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TY  - JOUR
AB  - 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.
AU  - Hodgson,J
AU  - Swietlik,EM
AU  - Salmon,RM
AU  - Hadinnapola,C
AU  - Nikolic,I
AU  - Wharton,J
AU  - Guo,J
AU  - Liley,J
AU  - Haimel,M
AU  - Bleda,M
AU  - Southgate,L
AU  - Machado,RD
AU  - Martin,JM
AU  - Treacy,CM
AU  - Yates,K
AU  - Daugherty,LC
AU  - Shamardina,O
AU  - Whitehorn,D
AU  - Holden,S
AU  - Bogaard,HJ
AU  - Church,C
AU  - Coghlan,G
AU  - Condliffe,R
AU  - Corris,PA
AU  - Danesino,C
AU  - Eyries,M
AU  - Gall,H
AU  - Ghio,S
AU  - Ghofrani,H-A
AU  - Gibbs,JSR
AU  - Girerd,B
AU  - Houweling,AC
AU  - Howard,L
AU  - Humbert,M
AU  - Kiely,DG
AU  - Kovacs,G
AU  - Lawrie,A
AU  - MacKenzie,Ross RV
AU  - Moledina,S
AU  - Montani,D
AU  - Olschewski,A
AU  - Olschewski,H
AU  - Ouwehand,WH
AU  - Peacock,AJ
AU  - Pepke-Zaba,J
AU  - Prokopenko,I
AU  - Rhodes,CJ
AU  - Scelsi,L
AU  - Seeger,W
AU  - Soubrier,F
AU  - Suntharalingam,J
AU  - Toshner,MR
AU  - Trembath,RC
AU  - Vonk,Noordegraaf A
AU  - Wort,SJ
AU  - Wilkins,MR
AU  - Yu,PB
AU  - Li,W
AU  - Gräf,S
AU  - Upton,PD
AU  - Morrell,NW
DO  - 10.1164/rccm.201906-1141OC
EP  - 585
PY  - 2020///
SN  - 1073-449X
SP  - 575
TI  - Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.201906-1141OC
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31661308
UR  - https://www.atsjournals.org/doi/10.1164/rccm.201906-1141OC
UR  - http://hdl.handle.net/10044/1/74421
VL  - 201
ER  -
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