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 dominan t familial erythrocytosis (FE), a benign clinical condition characterized b y hypersensitivity of erythroid progenitor cells to EPO and low serum EPO ( S-EPO) levels. We describe a Swedish family with dominant FE in which eryth rocytosis segregates with a new truncation in the negative control domain o f the EPOR, We show that cells engineered to concomitantly express the wild -type (WT) EPOR and mutant EPORs associated with FE (FE EPORs) are hypersen sitive to EPO-stimulated proliferation and activation of Jak2 and Stat5, Th ese results demonstrate that FE is caused by hyperresponsiveness of recepto r-mediated signaling pathways and that this is dominant with respect to WT EPOR signaling. (C) 1999 by The American Society of Hematology.