A nonsynonymous LNK polymorphism associated with idiopathic erythrocytosis.

Idiopathic erythrocytosis (IE) comprises a heterogeneous group of disorders characterized by hyperplasia of the erythroid lineage; however, in many cases, the molecular basis remains undetermined. Serum erythropoietin (EPO) levels can be raised, normal, or reduced, suggesting that there are at least two underlying etiologies involving either the control of EPO production or modulation of EPO-induced signaling. EPO production is regulated by the oxygen-sensing pathway via the hypoxia inducible transcription factor (HIF) complex. Proteasomal turnover of HIF is controlled by interactions with the von Hippel Lindau (VHL) and prolyl hydroxylase domain 2 (PHD2) proteins. Erythrocytosis-associated mutations have been detected in the oxygen sensing pathway indicating that EPO is regulated by the HIF-2alpha-PHD2-VHL axis (reviewed by McMullin [1]). Aberrant EPO-induced signaling in IE patients with subnormal serum EPO levels can arise from mutations in the EPO receptor (EpoR) gene which result in the receptor being hypersensitive to EPO with prolonged activation of the EPO-dependent signaling pathways (reviewed by Percy [2]).