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Cardiopulmonary phenotype associated with human PHD2 mutation.

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cam.issuedOnline2017-04-10
dc.contributor.authorTalbot, Nick P
dc.contributor.authorSmith, Thomas G
dc.contributor.authorBalanos, George M
dc.contributor.authorDorrington, Keith L
dc.contributor.authorMaxwell, Patrick H
dc.contributor.authorRobbins, Peter A
dc.contributor.orcidTalbot, Nick P [0000-0002-9186-8950]
dc.date.accessioned2018-10-10T05:16:35Z
dc.date.available2018-10-10T05:16:35Z
dc.date.issued2017-04
dc.description.abstractOxygen-dependent regulation of the erythropoietin gene is mediated by the hypoxia-inducible factor (HIF) family of transcription factors. When oxygen is plentiful, HIF undergoes hydroxylation by a family of oxygen-dependent prolyl hydroxylase domain (PHD) proteins, promoting its association with the von Hippel-Lindau (VHL) ubiquitin E3 ligase and subsequent proteosomal degradation. When oxygen is scarce, the PHD enzymes are inactivated, leading to HIF accumulation and upregulation not only of erythropoietin expression, but also the expression of hundreds of other genes, including those coordinating cardiovascular and ventilatory adaptation to hypoxia. Nevertheless, despite the identification of over 50 mutations in the PHD-HIF-VHL pathway in patients with previously unexplained congenital erythrocytosis, there are very few reports of associated cardiopulmonary abnormalities. We now report exaggerated pulmonary vascular and ventilatory responses to acute hypoxia in a 35-year-old man with erythrocytosis secondary to heterozygous mutation in PHD2, the most abundant of the PHD isoforms. We compare this phenotype with that reported in patients with the archetypal disorder of cellular oxygen sensing, Chuvash polycythemia, and discuss the possible clinical implications of our findings, particularly in the light of the emerging role for small molecule PHD inhibitors in clinical practice.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.30712
dc.identifier.eissn2051-817X
dc.identifier.issn2051-817X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283344
dc.languageeng
dc.language.isoeng
dc.publisherWiley
dc.publisher.urlhttp://dx.doi.org/10.14814/phy2.13224
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHypoxia
dc.subjecthypoxia‐inducible factor
dc.subjectprolyl hydroxylase domain protein
dc.subjectpulmonary circulation
dc.subjectventilation
dc.subjectAdult
dc.subjectBlood Pressure
dc.subjectCardiac Output
dc.subjectEchocardiography, Doppler
dc.subjectForced Expiratory Volume
dc.subjectHeart Rate
dc.subjectHumans
dc.subjectHypoxia
dc.subjectHypoxia-Inducible Factor-Proline Dioxygenases
dc.subjectMale
dc.subjectMutation
dc.subjectPhenotype
dc.subjectPolycythemia
dc.subjectSpirometry
dc.titleCardiopulmonary phenotype associated with human PHD2 mutation.
dc.typeArticle
dcterms.dateAccepted2017-02-23
prism.issueIdentifier7
prism.publicationDate2017
prism.publicationNamePhysiol Rep
prism.volume5
pubs.funder-project-idWellcome Trust (096956/Z/11/Z)
rioxxterms.licenseref.startdate2017-04
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.14814/phy2.13224

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