EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.

Authors: Perrotta, S  Cucciolla, V  Ferraro, M  Ronzoni, L  Tramontano, A  Rossi, F  Scudieri, AC  Borriello, A  Roberti, D  Nobili, B  Cappellini, MD  Oliva, A  Amendola, G  Migliaccio, AR  Mancuso, P  Martin-Padura, I  Bertolini, F  Yoon, D  Prchal, JT  Della Ragione, F 
Citation: Perrotta S, etal., PLoS One. 2010 Aug 5;5(8):e12015. doi: 10.1371/journal.pone.0012015.
Pubmed: (View Article at PubMed) PMID:20700488
DOI: Full-text: DOI:10.1371/journal.pone.0012015

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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.


Disease Annotations
Objects Annotated

Additional Information

CRRD Object Information
CRRD ID: 11041601
Created: 2016-03-24
Species: All species
Last Modified: 2016-03-24
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.