New Erythropoietin Gene Variants Linked to Hereditary Erythrocytosis

Erythrocytosis, a condition marked by the overproduction of red blood cells (RBCs), can be either congenital or acquired. Erythropoietin (EPO), the primary hormone regulating RBC production, is controlled by a tightly regulated negative feedback loop. Under hypoxic conditions, the EPO promoter is activated, leading to increased transcription of the EPO locus resulting in increased production of EPO and subsequent rise in RBCs. Although mutations in genes within this oxygen-sensing pathway may lead to hereditary erythrocytosis, the exact molecular mechanism often remains unclear. In a recent study, researchers sequenced the EPO locus and related hypoxia-pathway genes from six families (29 patients) with unexplained erythrocytosis. They identified three genetic variants in noncoding regions of EPO—one in the promoter and two different variants in intron 1. All three variants showed increased expression in cell lines under hypoxic conditions, had distinct biochemical and pH profiles similar to fetal liver-derived EPO, and had enhanced activity compared to healthy controls. The study also identified new regulatory regions of the EPO promoter, which may lead to new therapies to regulate EPO expression. Further investigation into novel variants of the EPO locus and other genes in the oxygen-sensing EPO pathway is needed.

References:

References:

1. McMullin MF. Erythrocytosis and variants of EPO. N Engl J Med 2025;392:1742-1745
2. Maric MD, Idriss S, Delamare M, Le Roy A, et al. Identification of hepatic-like EPO as a cause of polycythemia. N Engl J Med 2025;392:1684-1697