EGLN1 mutations in Cis can induce congenital erythrocytosis with thromboses by increasing protein instability

Abstract

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.