Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia
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| 024 | 7 | 0 | |a 10.1007/s00109-014-1205-7 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00109-014-1205-7 | ||
| 245 | 0 | 0 | |a Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia |h [Elektronische Daten] |c [Chunzhang Yang, Zhengping Zhuang, Stephanie Fliedner, Uma Shankavaram, Michael Sun, Petra Bullova, Roland Zhu, Abdel Elkahloun, Peter Kourlas, Maria Merino, Electron Kebebew, Karel Pacak] |
| 520 | 3 | |a 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. | |
| 540 | |a Springer-Verlag Berlin Heidelberg (outside the USA), 2014 | ||
| 690 | 7 | |a Paraganglioma |2 nationallicence | |
| 690 | 7 | |a Pheochromocytoma |2 nationallicence | |
| 690 | 7 | |a Polycythemia |2 nationallicence | |
| 690 | 7 | |a Erythropoietin |2 nationallicence | |
| 700 | 1 | |a Yang |D Chunzhang |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Zhuang |D Zhengping |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Fliedner |D Stephanie |u 1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany |4 aut | |
| 700 | 1 | |a Shankavaram |D Uma |u Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Sun |D Michael |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Bullova |D Petra |u 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 |4 aut | |
| 700 | 1 | |a Zhu |D Roland |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Elkahloun |D Abdel |u Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Kourlas |D Peter |u Columbus Hematology and Oncology Associates, Columbus, OH, USA |4 aut | |
| 700 | 1 | |a Merino |D Maria |u Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Kebebew |D Electron |u Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | |
| 700 | 1 | |a Pacak |D Karel |u 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 |4 aut | |
| 773 | 0 | |t Journal of Molecular Medicine |d Springer Berlin Heidelberg |g 93/1(2015-01-01), 93-104 |x 0946-2716 |q 93:1<93 |1 2015 |2 93 |o 109 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00109-014-1205-7 |q text/html |z Onlinezugriff via DOI |
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| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00109-014-1205-7 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Yang |D Chunzhang |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhuang |D Zhengping |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Fliedner |D Stephanie |u 1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Shankavaram |D Uma |u Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Sun |D Michael |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Bullova |D Petra |u 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 |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhu |D Roland |u Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Elkahloun |D Abdel |u Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Kourlas |D Peter |u Columbus Hematology and Oncology Associates, Columbus, OH, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Merino |D Maria |u Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Kebebew |D Electron |u Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Pacak |D Karel |u 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 |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Medicine |d Springer Berlin Heidelberg |g 93/1(2015-01-01), 93-104 |x 0946-2716 |q 93:1<93 |1 2015 |2 93 |o 109 | ||