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dc.contributor.authorHodgson, Joshua
dc.contributor.authorRuiz-Llorente, Lidia
dc.contributor.authorMcDonald, Jamie
dc.contributor.authorQuarrell, Oliver
dc.contributor.authorUgonna, Kelechi
dc.contributor.authorBentham, James
dc.contributor.authorMason, Rebecca
dc.contributor.authorMartin, Jennifer
dc.contributor.authorMoore, David
dc.contributor.authorBergstrom, Katie
dc.contributor.authorBayrak-Toydemir, Pinar
dc.contributor.authorWooderchak-Donahue, Whitney
dc.contributor.authorMorrell, Nicholas
dc.contributor.authorCondliffe, Robin
dc.contributor.authorBernabeu, Carmelo
dc.contributor.authorUpton, Paul
dc.date.accessioned2022-01-05T16:28:40Z
dc.date.available2022-01-05T16:28:40Z
dc.date.issued2021-12
dc.date.submitted2020-12-06
dc.identifier.issn2324-9269
dc.identifier.othermgg31685
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332039
dc.description.abstractBACKGROUND: Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra-rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases. METHODS: Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE-luciferase reporter cell line (HMEC1-BRE). Proteins were expressed for assessment of secretion and processing. RESULTS: Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum-derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9. CONCLUSION: Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or "HHT-like" telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs.
dc.languageen
dc.publisherWiley
dc.subjectORIGINAL ARTICLE
dc.subjectORIGINAL ARTICLES
dc.subjectbone morphogenetic protein
dc.subjecthereditary hemorrhagic telangiectasia
dc.subjectpulmonary arterial hypertension
dc.subjectpulmonary arteriovenous malformations
dc.titleHomozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children.
dc.typeArticle
dc.date.updated2022-01-05T16:28:40Z
prism.issueIdentifier12
prism.publicationNameMol Genet Genomic Med
prism.volume9
dc.identifier.doi10.17863/CAM.79486
dcterms.dateAccepted2021-03-22
rioxxterms.versionofrecord10.1002/mgg3.1685
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHodgson, Joshua [0000-0001-8423-0935]
dc.contributor.orcidRuiz-Llorente, Lidia [0000-0003-1430-9618]
dc.contributor.orcidMcDonald, Jamie [0000-0001-9939-7922]
dc.contributor.orcidQuarrell, Oliver [0000-0002-3818-9051]
dc.contributor.orcidMartin, Jennifer [0000-0002-7697-7438]
dc.contributor.orcidMoore, David [0000-0001-9308-5741]
dc.contributor.orcidBergstrom, Katie [0000-0002-0353-2278]
dc.contributor.orcidBayrak-Toydemir, Pinar [0000-0001-9381-2478]
dc.contributor.orcidWooderchak-Donahue, Whitney [0000-0002-9358-7466]
dc.contributor.orcidMorrell, Nicholas [0000-0001-5700-9792]
dc.contributor.orcidCondliffe, Robin [0000-0002-3492-4143]
dc.contributor.orcidBernabeu, Carmelo [0000-0002-1563-6162]
dc.contributor.orcidUpton, Paul [0000-0003-2716-4921]
dc.identifier.eissn2324-9269
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (RG/19/3/34265)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idMedical Research Council (MR/K020919/1)
pubs.funder-project-idBritish Heart Foundation (SP/18/10/33975)
cam.issuedOnline2021-04-09


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