Two new mutations in the HIF2A gene associated with erythrocytosis

Am J Hematol. 2012 Apr;87(4):439-42. doi: 10.1002/ajh.23123. Epub 2012 Feb 24.


Congenital or familial erythrocytosis/polycythemia can have many causes, and an emerging cause is genetic disruption of the oxygen-sensing pathway that regulates the ERYTHROPOIETIN (EPO) gene. More specifically, recent studies have identified erythrocytosis-associated mutations in the HIF2A gene, which encodes for Hypoxia Inducible Factor-2α (HIF-2α), as well as in two genes that encode for proteins that regulate it, Prolyl Hydroxylase Domain protein 2 (PHD2) and the von Hippel Lindau tumor suppressor protein (VHL). We report here the identification of two new heterozygous HIF2A missense mutations, M535T and F540L, both associated with erythrocytosis. Met-535 has previously been identified as a residue mutated in other patients with erythrocytosis, although the mutation of this particular residue to Thr has not been reported. In contrast, Phe-540 has not been reported as a residue mutated in erythrocytosis, and we present evidence here that this mutation impairs interaction of HIF-2α with both VHL and PHD2.

Publication types

  • Case Reports
  • Letter

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Conserved Sequence
  • Erythropoietin / physiology
  • Exons / genetics
  • Female
  • Heterozygote
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense*
  • Point Mutation*
  • Polycythemia / congenital*
  • Polycythemia / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Protein Interaction Mapping
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Erythropoietin
  • endothelial PAS domain-containing protein 1
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human

Supplementary concepts

  • Polycythemia, primary familial and congenital