The effect on erythrocytosis remains unexplained; HIF-2 is now considered the primary regulator of adult erythropoiesis through its regulation of EPO production, based on studies of conditional knockout mice (3) and studies demonstrating that missense mutations in the HIF pathway that increase HIF-2α expression result in the phenotypic triad of hereditary erythrocytosis, pulmonary hypertension, and thrombosis in humans and mice (4). The gene discussed is EPAS1; the disease is pulmonary hypertension.