Mutations in the EGLN1 (also known as PHD2) gene are associated with erythrocytosis. 1 The encoded protein, PHD2, is a central cellular oxygen sensor that hydroxylates the a subunit of the hypoxia inducible factor (HIF) transcription factor complex, marking it for degradation. 2-4 HIF controls red cell mass principally through upregulation of the ERYTHROPOIETIN (EPO) gene. 5 All functionally characterized erythrocytosis-associated mutations in the EGLN1 gene described to date are heterozygous loss-of-function mutations that reside near or within the prolyl hydroxylase domain. 6-11 However, PHD2 also contains a MYND-type zinc finger. 12, 13 Differing functions of this domain have been characterized, and it has been proposed to have either a positive or a negative regulatory function. 14-16 The importance of the zinc finger in humans is not known. Here, we report a human PHD2 zinc finger mutation associated with congenital erythrocytosis and its functional characterization. We find that this mutation produces a loss of function. This therefore supports the notion that the zinc finger ordinarily has a positive regulatory function and plays a role in the oxygen-sensing pathway that regulates erythropoiesis in humans.

The index case is a 14-year-old daughter of healthy consanguineous parents (first cousins) referred to a pediatrician because of persistent abdominal pain and fatigue. A general screening blood test revealed a hemoglobin (Hb) level of 18 g/dL (reference value 11.4-14.5 g/dL)(Table 1). Additional blood tests by a pediatric hematologist showed an elevated hematocrit Hct of 0.54 (reference value 0.37-0.45), RBC of 6.46 million/mL, WBC of 7.1 3 109/L, platelets of 217 3 109/L, and a low EPO of 6.0 mU/mL (reference value 9-28 mU/mL). Subsequent evaluation by a