Disturbance in the HIF-1α pathway associated with erythrocytosis: Further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene

The hypoxia-inducible factor HIF-1 is the key regulator in cellular adaptation to hypoxia. Acting through a complex pathway, interconnected with VHL and kinases, it regulates a large number of genes, such as those involved in erythropoiesis, glycolysis, pH regulation, and angiogenesis. Recently, a missense mutation [c.950C>G (p.Pro317Arg)] in the prolyl hydroxylase domain protein 2 (PHD2) gene, whose encoded protein has HIF-1α as a substrate, provided evidence of the PHD2 role in a case of familial erythrocytosis. In this study, we looked for mutations in the PHD2 gene, in 74 patients with unidentified erythrocytosis. We found two heterozygous carriers of frameshift mutations [c.606delG (p.Met202IlefsX71) and c.840_841insA (p.Arg281ThrfsX3)]; both located in exon 1 and a heterozygous carrier of a nonsense mutation [c.1129C>T (p. Gln377X)] in exon 3. As a result of these mutations the encoded PHD2, if synthesized, would lose its catalytic activity. The genetic defects herein described are the first frameshift and nonsense mutations reported in the PHD2 gene and, as the previous missense mutation described, suggest that a decreased prolyl hydroxylase activity disturbing the oxygen-sensing pathway might be the cause of erythrocytosis. In addition to erythrocytosis, other complications, such as inflammatory arthromyalgia, have been observed in one case.