Hemoglobin Rainier (beta(145) tyrosine-->histidine) is an abnormal hemoglobin associated with increased oxygen affinity, decreased heme-heme interaction, presence of a Bohr effect, and erythrocytosis, but without obvious clinical sequelae. Regulation of erythropoiesis was studied in affected members of families having either hemoglobin Rainier or Yakima, abnormal hemoglobins associated with ery...

\TO CLASSES of amino acid substitutions in hemoglobins have profound effects on the major function of this protein, oxygen transport. The first includes the hemoglobins M’ and hemoglobin Kansas,2 which result in cyanoSis in heterozygous subjects and no significant erythrocytosis. The second class, represented by hemoglobin Chesapeake3 and hemoglobin Yakima,4 is assocated with erythrocytosis in ...

1. Ang SO, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet. 2002;32:614-621. 2. Percy MJ, Zhao Q, Flores A, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006;103:654-659. 3. Percy MJ, Furlow PW, Lucas GS, et al. A gain-of-function muta...

HIF2A transcription factor plays a central role in the regulation of the hypoxia responding pathway in mammalian cells, by modulating erythropoiesis and angiogenesis. Molecular alterations of oxygen sensing pathway constituents are implicated in hereditary erythrocytosis. Here we show that 2 members of a family with idiopathic erythrocytosis exhibited a new heterozygous G to A mutation at base ...

A review of the pertinent literature on the relation of erythropoietin production to the presence of renal neoplasm suggests that erythropoietin may be produced either directly by the tumor or indirectly by its physical effect on the adjoining normal renal tissue. The most commonly found tumors which are associated with elevated levels of serum and urinary erythropoietin are the hypernephromas....

BACKGROUND Increased red blood cell count (Erythrocytosis) is an important paraneoplastic syndrome of hepatocellular carcinoma (HCC) and is a significant risk factor for lethal lung artery thromboembolism. HCC-associated erythrocytosis is partially caused by the ability of several HCC cells to produce erythropoietin (EPO). Prolyl-4-hydroxylase 2 (PHD2) is an enzyme encoded by the gene EGLN1. Th...

Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2α, elevated levels of serum erythropoietin, and erythrocytosis/polycythemia. This phenotype is recapitulated by a mouse model bearing a homozygous VhlR200W mutation. We previously showed that iron-regulatory protein 1-knockout (Irp1-knockout) mice developed ...

Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show th...

The ERYTHROPOIETIN (EPO) gene is regulated by the transcription factor Hypoxia Inducible Factor-alpha (HIF-alpha). In this pathway, Prolyl Hydroxylase Domain protein 2 (PHD2) hydroxylates two prolyl residues in HIF-alpha, which in turn promotes HIF-alpha degradation by the von Hippel Lindau (VHL) protein. Evidence that HIF-2alpha is the important isoform for EPO regulation in humans comes from ...

OBJECTIVES Cocaine-mediated erythrocytosis is one of several effects that cocaine may have on hematologic indices; however, the precise mechanism by which cocaine induces peripheral erythrocytosis is not fully understood. The objective of this study was to examine the contribution of the bone marrow to cocaine-mediated erythrocytosis. METHODS Differences in mean hemoglobin concentration, hema...