Abstract

Summary Hereditary congenital erythrocytosis results from constitutive activation of the hypoxia pathway. This pathway is controlled by regulation of the α isoforms of the hypoxia‐inducible factor α/β heterodimer, notably via hydroxylation by prolyl hydroxylase domain 2 (PHD2). Mutations affecting PHD2 are involved in Type 3 erythrocytosis. We report an atypical family bearing two PHD2 mutations located in Cis (L195H and E225D) transmitted in a dominant feature, together with a phenotypic analysis, structural modelling and functional study. Mutations have a cumulative effect, with E255D playing the major role, and severely compromised PHD2 stability, probably explaining why the hypoxia pathway at the origin of the disease is activated.