期刊
HAEMATOLOGICA
卷 98, 期 10, 页码 1624-1632出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2013.088369
关键词
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类别
资金
- Progetti di Rilevante Interesse Nazionale, PRIN
- Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica of the Second University of Naples (Normal and Pathological Hematopoiesis)
- Regione Campania Laboratorio pubblico per l'identificazione di inibitori del pathway dell'oxygen sensing per la terapia di malattie rare
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [11653]
- NCCR Kidney.CH
- SNF
- [31003A_129962/1]
Hypoxia-inducible factor 2 alpha (HIF-2 alpha) 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-2 alpha transcription factors, indicated that these genetic alterations lead to the stabilization of HIF-2 alpha 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-2 alpha 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.
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