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EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.
- Source :
-
PloS one [PLoS One] 2010 Aug 05; Vol. 5 (8), pp. e12015. Date of Electronic Publication: 2010 Aug 05. - Publication Year :
- 2010
-
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.<br />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.<br />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.
- Subjects :
- Adolescent
Adult
Base Sequence
Case-Control Studies
Cell Membrane pathology
Cell Proliferation
Child, Preschool
Cytoplasm metabolism
Endothelial Cells metabolism
Erythroid Precursor Cells metabolism
Erythroid Precursor Cells pathology
Female
Humans
K562 Cells
Male
Middle Aged
Mutation
Phenotype
Phosphorylation
Polycythemia blood
Polycythemia metabolism
Protein Structure, Tertiary
Receptors, Erythropoietin chemistry
Receptors, Erythropoietin genetics
STAT5 Transcription Factor metabolism
Young Adult
Antigens, CD34 metabolism
Cell Differentiation
Endothelial Cells pathology
Polycythemia genetics
Polycythemia pathology
Receptors, Erythropoietin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 5
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 20700488
- Full Text :
- https://doi.org/10.1371/journal.pone.0012015