{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T23:35:07Z","timestamp":1769124907019,"version":"3.49.0"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,3,9]],"date-time":"2011-03-09T00:00:00Z","timestamp":1299628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/us\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["075876"],"award-info":[{"award-number":["075876"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["TG092416"],"award-info":[{"award-number":["TG092416"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2011,6]]},"abstract":"<jats:p>\n                    The hypoxia\u2010inducible factors (HIFs; isoforms HIF\u20101\u03b1, HIF\u20102\u03b1, HIF\u20103\u03b1) mediate many responses to hypoxia. Their regulation is principally by oxygen\u2010dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel\u2010Lindau (VHL) protein. Chuvash polycythe\u2010mia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF\u20102\u03b1 gain\u2010of\u2010function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF\u20102\u03b1 gain\u2010of\u2010function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF\u20102\u03b1 gain\u2010of\u2010function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild\u2010type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF\u20102\u03b1 gain\u2010of\u2010function phenotype may be more limited than the Chuvash phenotype either because HIF\u20101\u03b1 is not elevated in the former condition, or because other HIF\u2010independent functions of VHL are perturbed in Chuvash polycythemia.\u2014Formenti, F., Beer, P. A., Croft, Q. P. P., Dorrington, K. L., Gale, D. P., Lappin, T. R J., Lucas, G. S., Maher, E. R, Maxwell, P. H., McMullin, M. F., O'Connor, D. F., Percy, M. J., Pugh, C. W., Ratcliffe, P. J., Smith, T. G., Talbot, N. P., Robbins, P. A. Cardiopulmonary function in two human disorders of the hypoxia\u2010inducible factor (HIF) pathway: von Hippel\u2010Lindau disease and HIF\u20102\u03b1 gain\u2010of\u2010function mutation.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    25, 2001\u20102011 (2011).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.10-177378","type":"journal-article","created":{"date-parts":[[2011,3,9]],"date-time":"2011-03-09T22:54:52Z","timestamp":1299711292000},"page":"2001-2011","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Cardiopulmonary function in two human disorders of the hypoxia\u2010inducible factor (HIF) pathway: von Hippel\u2010Lindau disease and HIF\u20102\u03b1 gain\u2010of\u2010function mutation"],"prefix":"10.1096","volume":"25","author":[{"given":"Federico","family":"Formenti","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy, and Genetics University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip A.","family":"Beer","sequence":"additional","affiliation":[{"name":"Department of Haematology Addenbrooke's Hospital and University of Cambridge Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quentin P. 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