EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>...
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Public Library of Science (PLoS)
2010
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oai:doaj.org-article:c749460bfd1e4e51998c1c626fd9cba62021-11-18T06:36:24ZEPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.1932-620310.1371/journal.pone.0012015https://doaj.org/article/c749460bfd1e4e51998c1c626fd9cba62010-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20700488/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Silverio PerrottaValeria CucciollaMarcella FerraroLuisa RonzoniAnnunziata TramontanoFrancesca RossiAnna Chiara ScudieriAdriana BorrielloDomenico RobertiBruno NobiliMaria Domenica CappelliniAdriana OlivaGiovanni AmendolaAnna Rita MigliaccioPatrizia MancusoInes Martin-PaduraFrancesco BertoliniDonghoon YoonJosef T PrchalFulvio Della RagionePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 8, p e12015 (2010) |
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Medicine R Science Q 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 EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Silverio Perrotta |
| title |
EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. |
| title_short |
EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. |
| title_full |
EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. |
| title_fullStr |
EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. |
| title_full_unstemmed |
EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. |
| title_sort |
epo receptor gain-of-function causes hereditary polycythemia, alters cd34 cell differentiation and increases circulating endothelial precursors. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/c749460bfd1e4e51998c1c626fd9cba6 |
| work_keys_str_mv |
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| _version_ |
1718424445450715136 |