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.

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.

• Authors: Silverio Perrotta, Valeria Cucciolla, Marcella Ferraro, Luisa Ronzoni, Annunziata Tramontano, Francesca Rossi, Anna Chiara Scudieri, Adriana Borriello, Domenico Roberti, Bruno Nobili, Maria Domenica Cappellini, Adriana Oliva, Giovanni Amendola, Anna Rita Migliaccio, Patrizia Mancuso, Ines Martin-Padura, Francesco Bertolini, Donghoon Yoon, Josef T Prchal, Fulvio Della Ragione
• Journal: PloS one (PLoS One) Vol. 5 Issue 8 Pg. e12015 (Aug 05 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20700488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Antigens, CD34
• Receptors, Erythropoietin
• STAT5 Transcription Factor

Topics

• Adolescent
• Adult
• Antigens, CD34 (metabolism)
• Base Sequence
• Case-Control Studies
• Cell Differentiation
• Cell Membrane (pathology)
• Cell Proliferation
• Child, Preschool
• Cytoplasm (metabolism)
• Endothelial Cells (metabolism, pathology)
• Erythroid Precursor Cells (metabolism, pathology)
• Female
• Humans
• K562 Cells
• Male
• Middle Aged
• Mutation
• Phenotype
• Phosphorylation
• Polycythemia (blood, genetics, metabolism, pathology)
• Protein Structure, Tertiary
• Receptors, Erythropoietin (chemistry, genetics, metabolism)
• STAT5 Transcription Factor (metabolism)
• Young Adult