Erythropoietin receptor mutations associated with familial erythrocytosis cause hypersensitivity to erythropoietin in the heterozygous state.
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.
Watowich
S S
SS
Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA.
Xie
X
X
Klingmuller
U
U
Kere
J
J
Lindlof
M
M
Berglund
S
S
de la Chapelle
A
A
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
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