EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.
PLoS One
; 5(8): e12015, 2010 Aug 05.
Article
en En
| MEDLINE
| ID: mdl-20700488
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/PRINCIPALFINDINGS:
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Policitemia
/
Diferenciación Celular
/
Receptores de Eritropoyetina
/
Antígenos CD34
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Células Endoteliales
Tipo de estudio:
Etiology_studies
/
Observational_studies
Límite:
Adolescent
/
Adult
/
Child, preschool
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Italia