Mutation Of Epo 5 ' Utr Facilitates Interaction With Hif2 And Causes Autosomal Dominant Erythrocytosis

We studied 10 affected and 11 non affected relatives of a five generation kindred with autosomal dominant familial erythrocytosis. We have excluded other known inherited forms of erythrocytosis. i.e., mutations of globin, the 2,3 DPG generating PBGM gene causing increased Hb/O2 affinity (low p50), gain-of-function mutations of erythropoietin receptor (EPOR), germ-line JAK2 mutations, and hypoxia inducible factor 2A (HIF2-A(EPAS1)), PHD2(EGLN1), and VHL mutations associated with augmented oxygen-sensing pathway. Those affected family members had moderately increased erythropoietin (EPO) levels, no splenomegaly, normal leukocyte and platelet numbers and normal p50 (presented at this mtg, Blood. 2003;102,162b). We sequenced whole exomes and adjacent portions of introns of two affected individuals and found a novel heterozygous 5'UTR EPO variant with change -136 nt upstream from the ATG EPO initiation site (NG_021471 -136 G>A). This variant segregated with the erythrocytosis phenotype in 15 relatives examined: the 7 affected subjects were heterozygous for this variant and the 8 unaffected were negative, suggesting its causative role in erythrocytosis (presented at this mtg, Blood. 2013;122,950).