title: EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.
abstract: BACKGROUND
  Gain-of-function of erythropoietin receptor (EPOR) mutations represent the major cause of primary hereditary polycythemia. EPOR is also found in non-erythroid tissues, although its physiological role is still undefined.
  
  
  RESULTS
  We describe a family with polycythemia due to a heterozygous mutation of the EPOR gene that causes a G-->T change at nucleotide 1251 of exon 8. The novel EPOR G1251T mutation results in the replacement of a glutamate residue by a stop codon at amino acid 393. Differently from polycythemia vera, EPOR G1251T CD34(+) cells proliferate and differentiate towards the erythroid phenotype in the presence of minimal amounts of EPO. Moreover, the affected individuals show a 20-fold increase of circulating endothelial precursors. The analysis of erythroid precursor membranes demonstrates a heretofore undescribed accumulation of the truncated EPOR, probably due to the absence of residues involved in the EPO-dependent receptor internalization and degradation. Mutated receptor expression in EPOR-negative cells results in EPOR and Stat5 phosphorylation. Moreover, patient erythroid precursors present an increased activation of EPOR and its effectors, including Stat5 and Erk1/2 pathway.
  
  
  CONCLUSIONS
  Our data provide an unanticipated mechanism for autosomal dominant inherited polycythemia due to a heterozygous EPOR mutation and suggest a regulatory role of EPO/EPOR pathway in human circulating endothelial precursors homeostasis.
authors.affiliation: Department of Pediatrics, Second University of Naples, Naples, Italy.
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.forename: Valeria
authors.initials: V
authors.lastname: Cucciolla
authors.forename: Marcella
authors.initials: M
authors.lastname: Ferraro
authors.forename: Luisa
authors.initials: L
authors.lastname: Ronzoni
authors.forename: Annunziata
authors.initials: A
authors.lastname: Tramontano
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Anna Chiara
authors.initials: AC
authors.lastname: Scudieri
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.forename: Domenico
authors.initials: D
authors.lastname: Roberti
authors.forename: Bruno
authors.initials: B
authors.lastname: Nobili
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Cappellini
authors.forename: Adriana
authors.initials: A
authors.lastname: Oliva
authors.forename: Giovanni
authors.initials: G
authors.lastname: Amendola
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancuso
authors.forename: Ines
authors.initials: I
authors.lastname: Martin-Padura
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Donghoon
authors.initials: D
authors.lastname: Yoon
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
mesh_terms: D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism*; D001483:Base Sequence; D016022:Case-Control Studies; D002454:Cell Differentiation; D002462:Cell Membrane / Q000473:pathology; D049109:Cell Proliferation; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011086:Polycythemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D017467:Receptors, Erythropoietin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor