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][7][8][9][10][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][15][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.

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