caa a22 4500 605542805 CHVBK 20210128100923.0 cr unu---uuuuu 210128e20150101xx s 000 0 eng 10.1007/s00109-014-1205-7 doi (NATIONALLICENCE)springer-10.1007/s00109-014-1205-7 Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia [Elektronische Daten] [Chunzhang Yang, Zhengping Zhuang, Stephanie Fliedner, Uma Shankavaram, Michael Sun, Petra Bullova, Roland Zhu, Abdel Elkahloun, Peter Kourlas, Maria Merino, Electron Kebebew, Karel Pacak] We have investigated genetic/pathogenetic factors associated with a new clinical entity in patients presenting with pheochromocytoma/paraganglioma (PHEO/PGL) and polycythemia. Two patients without hypoxia-inducible factor 2α (HIF2A) mutations, who presented with similar clinical manifestations, were analyzed for other gene mutations, including prolyl hydroxylase (PHD) mutations. We have found for the first time a germ-line mutation in PHD1 in one patient and a novel germ-line PHD2 mutation in a second patient. Both mutants exhibited reduced protein stability with substantial quantitative protein loss and thus compromised catalytic activities. Due to the unique association of patients' polycythemia with borderline or mildly elevated erythropoietin (EPO) levels, we also performed an in vitro sensitivity assay of erythroid progenitors to EPO and for EPO receptor (EPOR) expression. The results show inappropriate hypersensitivity of erythroid progenitors to EPO in these patients, indicating increased EPOR expression/activity. In addition, the present study indicates that HIF dysregulation due to PHD mutations plays an important role in thepathogenesis of these tumors and associated polycythemia. The PHD1 mutation appears to be a new member contributing to the genetic landscape of this novel clinical entity. Our results support the existence of a specific PHD1- and PHD2-associated PHEO/PGL-polycythemia disorder. Key message: • A novel germ-line PHD1 mutation causing pheochromocytoma/paraganglioma and polycythemia. • Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO. Springer-Verlag Berlin Heidelberg (outside the USA), 2014 Paraganglioma nationallicence Pheochromocytoma nationallicence Polycythemia nationallicence Erythropoietin nationallicence Yang Chunzhang Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut Zhuang Zhengping Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut Fliedner Stephanie 1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany aut Shankavaram Uma Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA aut Sun Michael Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut Bullova Petra Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1E-3140, 10 Center Drive, MSC-1109, 20892-1109, Bethesda, MD, USA aut Zhu Roland Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut Elkahloun Abdel Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA aut Kourlas Peter Columbus Hematology and Oncology Associates, Columbus, OH, USA aut Merino Maria Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA aut Kebebew Electron Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA aut Pacak Karel Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1E-3140, 10 Center Drive, MSC-1109, 20892-1109, Bethesda, MD, USA aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/1(2015-01-01), 93-104 0946-2716 93:1<93 2015 93 109 https://doi.org/10.1007/s00109-014-1205-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-014-1205-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yang Chunzhang Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Zhuang Zhengping Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Fliedner Stephanie 1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany aut NATIONALLICENCE 700 1- Shankavaram Uma Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Sun Michael Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Bullova Petra Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1E-3140, 10 Center Drive, MSC-1109, 20892-1109, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Zhu Roland Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Elkahloun Abdel Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Kourlas Peter Columbus Hematology and Oncology Associates, Columbus, OH, USA aut NATIONALLICENCE 700 1- Merino Maria Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Kebebew Electron Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Pacak Karel Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1E-3140, 10 Center Drive, MSC-1109, 20892-1109, Bethesda, MD, USA aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/1(2015-01-01), 93-104 0946-2716 93:1<93 2015 93 109