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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Gräf, S; Haimel, M; Bleda, M; Hadinnapola, C; Southgate, L; Li, W; Hodgson, J; Liu, B; Salmon, RM; Southwood, M; et al. Gräf, S; Haimel, M; Bleda, M; Hadinnapola, C; Southgate, L; Li, W; Hodgson, J; Liu, B; Salmon, RM; Southwood, M; Machado, RD; Martin, JM; Treacy, CM; Yates, K; Daugherty, LC; Shamardina, O; Whitehorn, D; Holden, S; Aldred, M; 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; MacKenzie Ross, RV; Moledina, S; Montani, D; Newnham, M; Olschewski, A; Olschewski, H; Peacock, AJ; Pepke-Zaba, J; Prokopenko, I; Rhodes, CJ; Scelsi, L; Seeger, W; Soubrier, F; Stein, DF; Suntharalingam, J; Swietlik, EM; Toshner, MR; van Heel, DA; Vonk Noordegraaf, A; Waisfisz, Q; Wharton, J; Wort, SJ; Ouwehand, WH; Soranzo, N; Lawrie, A; Upton, PD; Wilkins, MR; Trembath, RC; Morrell, NW (2018) Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun, 9 (1). p. 1416. ISSN 2041-1723 https://doi.org/10.1038/s41467-018-03672-4
SGUL Authors: Southgate, Laura

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Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2018
Keywords: MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
Dates:
DateEvent
12 April 2018Published
2 March 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
R01 HL098199NHLBI NIH HHSUNSPECIFIED
SP/12/12/29836British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MR/K020919/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG/08/006/25302British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/13/4/30107British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MGU0205Bart's CharityUNSPECIFIED
204809/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
FS/15/59/31839British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/13/48/30453British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 29650961
Web of Science ID: WOS:000429794300009
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109736
Publisher's version: https://doi.org/10.1038/s41467-018-03672-4

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