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Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range
- Publication Year :
- 2013
-
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. © 2013 Ferrata Storti Foundation.
- Subjects :
- Adult
Male
Adolescent
2720 Hematology
Red Cells
Basic Helix-Loop-Helix Transcription Factor
Molecular Sequence Data
Mutation, Missense
610 Medicine & health
Polycythemia
Biology
Gene mutation
medicine.disease_cause
10052 Institute of Physiology
Cohort Studies
Reference Values
medicine
Basic Helix-Loop-Helix Transcription Factors
Missense mutation
Humans
Hematopoiesi
Reference Value
Amino Acid Sequence
Transcription factor
Erythropoietin
Genetics
Mutation
Hematopoietic Stem Cell
Articles
Biomarker
Hematology
Phenotype
Haematopoiesis
10076 Center for Integrative Human Physiology
Cancer research
570 Life sciences
biology
Erythropoiesis
Cohort Studie
Biomarkers
medicine.drug
Human
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....6468479d4ec2eba8b84644c4a2f0a914