{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T11:04:06Z","timestamp":1781780646871,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012953","name":"Communaut\u00e9 Universit\u00e9 Grenoble Alpes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012953","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015400","name":"Fonds Erasme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015400","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pulmonary arterial hypertension (PAH) is a rare and severe disorder characterized by progressive pulmonary vasculopathy. <jats:italic>Growth differentiation factor<\/jats:italic> (<jats:italic>GDF<\/jats:italic>)<jats:italic>2<\/jats:italic> encodes the pro\u2010protein bone morphogenetic protein (BMP) 9, activated after cleavage by endoproteases into an active mature form. BMP9, together with BMP10, are high\u2010affinity ligands of activin receptor\u2010like kinase 1 (ALK1) and BMP receptor type II (BMPR2). <jats:italic>GDF2<\/jats:italic> mutations have been reported in idiopathic PAH with most patients being heterozygous carriers although rare homozygous cases have been described. The link between PAH occurrence and BMP9 or 10 expression level is still unclear. In this study, we describe a pediatric case of PAH also presenting with telangiectasias and epistaxis. The patient carries the novel homozygous <jats:italic>GDF2<\/jats:italic> c.946A\u2009&gt;\u2009G mutation, replacing the first arginine of BMP9's cleavage site (R316) by a glycine. We show that this mutation leads to an absence of circulating mature BMP9 and mature BMP9\u201010 heterodimers in the patient's plasma although pro\u2010BMP9 is still detected at a similar level as controls. In vitro functional studies further demonstrated that the mutation R316G hampers the correct processing of BMP9, leading to the secretion of inactive pro\u2010BMP9. The heterozygous carriers of the variant were asymptomatic, similarly to previous reports, reinforcing the hypothesis of modifiers preventing\/driving PAH development in heterozygous carriers.<\/jats:p>","DOI":"10.1002\/ajmg.a.63236","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T10:13:50Z","timestamp":1685441630000},"page":"2064-2073","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pediatric pulmonary arterial hypertension due to a novel homozygous <scp><i>GDF2<\/i><\/scp> missense variant affecting <scp>BMP9<\/scp> processing and activity"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8227-9281","authenticated-orcid":false,"given":"L.","family":"Chomette","sequence":"first","affiliation":[{"name":"Department of Cardiology, H\u00f4pital Erasme, H\u00f4pital Universitaire de Bruxelles Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"},{"name":"IRIBHM, Faculty of medicine Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Hupkens","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology and Pharmacology (LAPP), Faculty of Medicine Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1402-7266","authenticated-orcid":false,"given":"M.","family":"Romitti","sequence":"additional","affiliation":[{"name":"IRIBHM, Faculty of medicine Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-1861","authenticated-orcid":false,"given":"L.","family":"Dewachter","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology and Pharmacology (LAPP), Faculty of Medicine Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6358-7852","authenticated-orcid":false,"given":"J. L.","family":"Vachi\u00e9ry","sequence":"additional","affiliation":[{"name":"Department of Cardiology, H\u00f4pital Erasme, H\u00f4pital Universitaire de Bruxelles Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1043-7030","authenticated-orcid":false,"given":"S.","family":"Bailly","sequence":"additional","affiliation":[{"name":"Laboratory BioSant\u00e9 Universit\u00e9 Grenoble Alpes, INSERM, CEA  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6869-9941","authenticated-orcid":false,"given":"S.","family":"Costagliola","sequence":"additional","affiliation":[{"name":"IRIBHM, Faculty of medicine Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2845-6758","authenticated-orcid":false,"given":"G.","family":"Smits","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, H\u00f4pital Erasme, H\u00f4pital Universitaire de Bruxelles Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0076-8007","authenticated-orcid":false,"given":"E.","family":"Tillet","sequence":"additional","affiliation":[{"name":"Laboratory BioSant\u00e9 Universit\u00e9 Grenoble Alpes, INSERM, CEA  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4103-515X","authenticated-orcid":false,"given":"Antoine","family":"Bondue","sequence":"additional","affiliation":[{"name":"Department of Cardiology, H\u00f4pital Erasme, H\u00f4pital Universitaire de Bruxelles Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"},{"name":"IRIBHM, Faculty of medicine Universit\u00e9 Libre de Bruxelles (ULB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61743"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62584"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-313314"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-034124"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.395"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01371-2018"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113178"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03672-4"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1685"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201906-1141OC"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700560"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)98867-8"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac237"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.229102"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.680009"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111023200"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2019-1970"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01899-2018"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.176601"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.314753"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002968"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62996"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-016-0183-7"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01609-2018"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.07.004"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0685-z"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63236","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T12:22:34Z","timestamp":1692793354000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,30]]},"references-count":28,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.1002\/ajmg.a.63236"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63236","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,30]]},"assertion":[{"value":"2023-01-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}