title: Erythropoietin receptor mutations associated with familial erythrocytosis cause hypersensitivity to erythropoietin in the heterozygous state.
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.
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Watowich
authors.forename: X
authors.initials: X
authors.lastname: Xie
authors.forename: U
authors.initials: U
authors.lastname: Klingmuller
authors.forename: J
authors.initials: J
authors.lastname: Kere
authors.forename: M
authors.initials: M
authors.lastname: Lindlof
authors.forename: S
authors.initials: S
authors.lastname: Berglund
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D004268:DNA-Binding Proteins / Q000097:blood; D004906:Erythrocyte Count; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004921:Erythropoietin / Q000097:blood* / Q000494:pharmacology*; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D053614:Janus Kinase 2; D007958:Leukocyte Count; D008297:Male; D008894:Milk Proteins; D009154:Mutation; D010375:Pedigree; D010976:Platelet Count; D011086:Polycythemia / Q000097:blood / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000097:blood; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin / Q000235:genetics*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2