Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene

Mutations causing truncations of the cytoplasmic domain of the human erythr opoietin receptor (EPOR) result in a dominantly inherited disorder-primary familiar congenital polycythemia, This disorder is characterized by increas ed numbers of erythrocytes (polycythemia) and by in vitro hypersensitivity of erythroid precursors to erythropoietin. The consequences of EPOR truncat ion in nonerythroid tissues are unknown. We replaced the murine EPOR gene w ith a wild-type human EPOR gene and a mutant human EPOR gene that we initia lly identified in a patient with polycythemia, This mutation leads to an EP OR truncated after the first tyrosine residue of the intracellular domain. Mice heterozygous for this mutant allele and a wild-type human EPOR allele mimicked the human disorder. Interestingly, mice that were homozygous for t he mutant human allele were severely polycythemic but viable. Our results p rovide a model for functional studies of EPOR-triggered signaling pathways in erythropoiesis. These animals can now be used to investigate the molecul ar pathophysiology of this gain-of-function EPOR mutation in erythroid tiss ue and in those nonerythroid tissues that express EPOR.