Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia
| Autor: | Chunzhang Yang, Stephanie M. J. Fliedner, Electron Kebebew, Roland Zhu, Peter J. Kourlas, Karel Pacak, Maria J. Merino, Petra Bullova, Abdel G. Elkahloun, Michael Sun, Uma Shankavaram, Zhengping Zhuang |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Mutant Pheochromocytoma Polycythemia Gene mutation medicine.disease_cause Hypoxia-Inducible Factor-Proline Dioxygenases Germline mutation Paraganglioma hemic and lymphatic diseases Internal medicine Drug Discovery Basic Helix-Loop-Helix Transcription Factors Receptors Erythropoietin medicine Humans Germ-Line Mutation Genetics (clinical) Mutation business.industry Middle Aged Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Erythropoietin receptor Endocrinology Erythropoietin Molecular Medicine Female business medicine.drug |
| Zdroj: | Journal of Molecular Medicine. 93:93-104 |
| ISSN: | 1432-1440 0946-2716 |
| DOI: | 10.1007/s00109-014-1205-7 |
| Popis: | 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 the pathogenesis 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.• A novel germ-l i n e PHD1 mutation causing heochromocytoma/paraganglioma and polycythemia. • Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO. |
| Databáze: | OpenAIRE |
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