| Mammalian cells are able to adapt to changes in oxygen tension due to the presence of a conserved oxygen sensing pathway. This pathway is critical in many physiological events arising from hypoxic stress, including vasculogenesis in embryo development and tumor formation. Dysregulation in the oxygen homeostasis can result in pathophysiological states, including polycythemia. Chuvash polycythemia (CP) is an autosomal recessive disorder characterized by elevated serum levels of erythropoietin (EPO), transferrin (Tf) and transferrin receptor (TfR), as well as hypersensitivity of erythroid progenitors to EPO. EPO, Tf and TfR are regulated by hypoxia-inducible factor (HIF) 1, the principal mediator of transcriptional responses in hypoxic cells. Epstein-Barr virus-transformed lymphocytes from patients with CP express higher levels of HIF-1alpha protein and glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF) and EPO messenger ribonucleic acids. Exploiting a presumed founder effect in the isolated Chuvash population for positional cloning, we mapped the CP gene locus to chromosome 3p25 and identified a C-to-T missense mutation in the yon Hippel-Lindau (VHL) gene, causing an arginine-to-tryptophan change at amino acid residue 200 (R200W). The VHL gene product negatively regulates hypoxia-inducible gene expression through the ubiquitination and subsequent destruction of HIF-1alpha. Our data indicate that the R200W mutation impairs the interaction of VHL with HIF-1alpha, perturbing the normally rapid degradation of HIF-1alpha and resulting in increased expression of downstream target genes, including EPO, GLUT1, Tf, TfR and VEGF. CP differs from the VHL syndromes described thus far by the homozygous rather than heterozygous germline VHL mutation and the presence of polycythemia rather than tumors as the predominant clinical manifestation. The lack of tumorigenesis in CP despite impaired VHL function differentiates the effects of R200W versus tumor-associated mutations, providing possible clues to the mechanisms of tumor suppression by VHL. Furthermore, CP is a unique type of polycythemia that provides new insights into the regulation of erythropoiesis and the molecular physiology of oxygen homeostasis. |
