Abstract
Inherited mutations in the erythropoietin receptor (EPOR) causing premature termination of the receptor cytoplasmic region are associated with dominant familial erythrocytosis (FE), a benign clinical condition characterized by hypersensitivity of erythroid progenitor cells to EPO and low serum EPO (S-EPO) levels. We describe a Swedish family with dominant FE in which erythrocytosis segregates with a new truncation in the negative control domain of the EPOR. We show that cells engineered to concomitantly express the wild-type (WT) EPOR and mutant EPORs associated with FE (FE EPORs) are hypersensitive to EPO-stimulated proliferation and activation of Jak2 and Stat5. These results demonstrate that FE is caused by hyperresponsiveness of receptor-mediated signaling pathways and that this is dominant with respect to WT EPOR signaling.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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DNA-Binding Proteins / blood
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Erythrocyte Count
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Erythroid Precursor Cells / drug effects*
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Erythroid Precursor Cells / pathology
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Erythroid Precursor Cells / physiology
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Erythropoietin / blood*
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Erythropoietin / pharmacology*
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Female
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Genes, Dominant
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Heterozygote
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Humans
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Janus Kinase 2
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Leukocyte Count
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Male
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Milk Proteins*
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Mutation
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Pedigree
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Platelet Count
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Polycythemia / blood
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Polycythemia / genetics*
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Protein-Tyrosine Kinases / blood
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Proto-Oncogene Proteins*
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Receptors, Erythropoietin / genetics*
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STAT5 Transcription Factor
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Trans-Activators / blood
Substances
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DNA-Binding Proteins
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Milk Proteins
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Proto-Oncogene Proteins
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Receptors, Erythropoietin
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STAT5 Transcription Factor
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Trans-Activators
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Erythropoietin
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2