{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:20:55Z","timestamp":1784557255512,"version":"3.55.0"},"reference-count":0,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2]]},"abstract":"\n Mosaic or somatic\n EPAS1<\/jats:italic>\n mutations are associated with a range of phenotypes including pheochromocytoma and\/or paraganglioma (PPGL), polycythemia and somatostatinoma. The pathogenic potential of germline\n EPAS1<\/jats:italic>\n variants however is not well understood. We report a number of germline\n EPAS1<\/jats:italic>\n variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies,\n EPAS1<\/jats:italic>\n \/HIF-2\u03b1 p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2\u03b1 Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with\n EPAS1<\/jats:italic>\n \/HIF-2\u03b1 p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline\n EPAS1<\/jats:italic>\n variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.\n <\/jats:p>","DOI":"10.1530\/erc-20-0280","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T06:42:03Z","timestamp":1607582523000},"page":"97-109","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":12,"title":["Functional significance of germline EPAS1 variants"],"prefix":"10.1530","volume":"28","author":[{"given":"Trisha","family":"Dwight","sequence":"first","affiliation":[{"name":"1Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia"},{"name":"2University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Kim","sequence":"additional","affiliation":[{"name":"1Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia"},{"name":"2University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Bastard","sequence":"additional","affiliation":[{"name":"1Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia"},{"name":"2University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana E","family":"Benn","sequence":"additional","affiliation":[{"name":"1Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia"},{"name":"2University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Eisenhofer","sequence":"additional","affiliation":[{"name":"3Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"},{"name":"4Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Richter","sequence":"additional","affiliation":[{"name":"3Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Mannelli","sequence":"additional","affiliation":[{"name":"5Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rapizzi","sequence":"additional","affiliation":[{"name":"5Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Prejbisz","sequence":"additional","affiliation":[{"name":"6Department of Hypertension, National Institute of Cardiology, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariola","family":"P\u0119czkowska","sequence":"additional","affiliation":[{"name":"6Department of Hypertension, National Institute of Cardiology, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Pacak","sequence":"additional","affiliation":[{"name":"7National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick","family":"Clifton-Bligh","sequence":"additional","affiliation":[{"name":"1Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia"},{"name":"2University of Sydney, Sydney, New South Wales, Australia"},{"name":"8Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/28\/2\/ERC-20-0280.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/28\/2\/ERC-20-0280.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:55:46Z","timestamp":1784555746000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/erc\/article\/28\/2\/97-109\/25543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2]]},"references-count":0,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.1530\/erc-20-0280","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2]]}}}