title: Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia.
abstract: 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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Stephanie M J
authors.initials: SM
authors.lastname: Fliedner
authors.forename: Uma
authors.initials: U
authors.lastname: Shankavaram
authors.forename: Michael G
authors.initials: MG
authors.lastname: Sun
authors.forename: Petra
authors.initials: P
authors.lastname: Bullova
authors.forename: Roland
authors.initials: R
authors.lastname: Zhu
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kourlas
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D008875:Middle Aged; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017467:Receptors, Erythropoietin; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C490190:EGLN1 protein, human; C447780:EGLN2 protein, human