title: Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range.
abstract: Hypoxia-inducible factor 2α (HIF-2α) plays a pivotal role in the balancing of oxygen requirements throughout the body. The protein is a transcription factor that modulates the expression of a wide array of genes and, in turn, controls several key processes including energy metabolism, erythropoiesis and angiogenesis. We describe here the identification of two cases of familial erythrocytosis associated with heterozygous HIF2A missense mutations, namely Ile533Val and Gly537Arg. Ile533Val is a novel mutation and represents the genetic HIF2A change nearest to Pro-531, the primary hydroxyl acceptor residue, so far identified. The Gly537Arg missense mutation has already been described in familial erythrocytosis. However, our patient is the only described case of a de novo HIF2A mutation associated with the development of congenital polycythemia. Functional in vivo studies, based on exogenous expression of hybrid HIF-2α transcription factors, indicated that these genetic alterations lead to the stabilization of HIF-2α protein. All the identified polycythemic subjects with HIF2A mutations show serum erythropoietin in the normal range, independently of the hematocrit values and phlebotomy frequency. The erythroid precursors obtained from the peripheral blood of patients showed an altered phenotype, including an increased rate of growth and a modified expression of some HIF-2α target genes. These results suggest the novel proposal that polycythemia observed in subjects with HIF2A mutations might also be due to primary changes in hematopoietic cells and not only secondary to increased erythropoietin levels.
authors.affiliation: silverio.perrotta@unina2.it or fulvio.dellaragione@unina2.it.
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stiehl
authors.forename: Francesca
authors.initials: F
authors.lastname: Punzo
authors.forename: Saverio
authors.initials: S
authors.lastname: Scianguetta
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.forename: Debora
authors.initials: D
authors.lastname: Bencivenga
authors.forename: Maddalena
authors.initials: M
authors.lastname: Casale
authors.forename: Bruno
authors.initials: B
authors.lastname: Nobili
authors.forename: Silvia
authors.initials: S
authors.lastname: Fasoli
authors.forename: Adriana
authors.initials: A
authors.lastname: Balduzzi
authors.forename: Lilla
authors.initials: L
authors.lastname: Cro
authors.forename: Katarzyna J
authors.initials: KJ
authors.lastname: Nytko
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D004921:Erythropoietin / Q000097:blood*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011086:Polycythemia / Q000097:blood / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D012016:Reference Values; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004921:Erythropoietin; D000099162:Endothelial PAS Domain-Containing Protein 1