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Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range


Perrotta, S; Stiehl, D P; Punzo, F; Scianguetta, S; Borriello, A; Bencivenga, D; Casale, M; Nobili, B; Fasoli, S; Balduzzi, A; Cro, L; Nytko, K J; Wenger, R H; Della Ragione, F (2013). Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range. Haematologica:1-34.

Abstract

Hypoxia-inducible factor 2α (HIF-2α) plays a pivotal role in the balancing of oxygen request 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. Gly537Arg missense mutation has been already described in familial erythrocytosis. However, our patient is the only described case of a de novo HIF2A mutation associated with congenital polycythemia development. 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 be also due to primary changes in hematopoietic cells and not only secondary to increased erythropoietin levels.

Hypoxia-inducible factor 2α (HIF-2α) plays a pivotal role in the balancing of oxygen request 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. Gly537Arg missense mutation has been already described in familial erythrocytosis. However, our patient is the only described case of a de novo HIF2A mutation associated with congenital polycythemia development. 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 be also due to primary changes in hematopoietic cells and not only secondary to increased erythropoietin levels.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:10 Oct 2013 15:14
Last Modified:05 Apr 2016 17:02
Publisher:Ferrata Storti Foundation
ISSN:0390-6078
Funders:Progetti di Rilevante Interesse Nazionale, PRIN, Dipt. della Donna, del Bambino e di Chirurgia Generale e Specialista, Second Univ. of Naples, Laboratorio pubblico per l'identificazione di inibitori del pathway dell'Oxygen Sensing per la terapia di malattie rare, Assoc. Italiana pr la Ricerca sul Cancro, Swiss National Science Foundation
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.3324
Permanent URL: https://doi.org/10.5167/uzh-81780

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