Erythrocytosis can arise from deregulation of the erythropoietin (Epo) axis resulting from defects in the oxygen-sensing pathway. Epo synthesis is controlled by the hypoxia inducible factor (HIF) complex, composed of an a and a ß subunit. There are 2 main a subunits, HIF-1a and HIF-2a. Recently, a HIF-2a Gly537Trp mutation was identified in a family with erythrocytosis. This raises the possibility of HIF2A mutations being associated with other cases of erythrocytosis. We now report a subsequent analysis of HIF2A in a cohort of 75 erythrocytosis patients and identify 4 additional patients with novel heterozygous Met535Val and Gly537Arg mutations. All patients presented at a young age with elevated serum Epo. Mutations at Gly-537 account for 4 of 5 HIF2A mutations associated with erythrocytosis. These findings support the importance of HIF-2a in human Epo regulation and warrant investigation of HIF2A in patients with unexplained erythrocytosis.
Percy, M. J., Beer, P. A., Campbell, G., Dekker, A. W., Green, A. R., Oscier, D., Rainey, M. G., Van Wijk, R., Wood, M., Lappin, T., McMullin, M., & Lee, F. S. (2008). Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood, 111(11), 5400-5402. https://doi.org/10.1182/blood-2008-02-137703