Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD, HIF2α, and VHL.
Direct sequencing analyses were performed on six genes associated with hereditary erythrocytosis [HBB, exon 2 and exon 3 of HBA2, VHL, EGLN1 (previously PHD2), exon 12 of EPAS1 (previously HIF2A), and exons 5-8 of EPOR].
This study provides a novel experimental system to study polycythaemia-inducing mutations in the EPOR, and sheds new light on underlying mechanisms of EPOR over-activation in PFCP patients.
These findings suggest that both tyrosine residues Y285 and Y344 in the cytoplasmic domain of EPOR-ME may contribute to increased Epo sensitivity that is characteristic of PFCP phenotype.
The finding of only five disease-causing mutations in our PFCP patient pool of 43 subjects (12%) indicates that EPOR gene mutations are not the major genetic defect associated with PFCP.
We show that cells engineered to concomitantly express the wild-type (WT) EPOR and mutant EPORs associated with FE (FEEPORs) are hypersensitive to EPO-stimulated proliferation and activation of Jak2 and Stat5.
These results suggest a role for Stat5 in regulation of Epo-mediated cell growth and implicate altered kinetics of Epo-induced Jak2 and Stat5 activation in the pathogenesis of familial erythrocytosis associated with this naturally occurring EpoR gene mutation.
Familial erythrocytosis, associated with high haemoglobin levels and low serum erythropoietin (Epo), has been shown to co-segregate with a sequence repeat polymorphism at the 5' region of the erythropoietin receptor (EpoR) in a large Finnish family.
Alterations of the EPO/EPO-R system have recently been shown to be involved in the pathogenesis of familial erythrocytosis and polycythaemia vera (PV).