Abstract
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.
MeSH terms
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Adult
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Amino Acid Sequence
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Amino Acid Substitution
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Base Sequence
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Basic Helix-Loop-Helix Transcription Factors / chemistry
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Conserved Sequence
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Erythropoietin / physiology
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Exons / genetics
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Female
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Heterozygote
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Humans
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Male
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Middle Aged
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Molecular Sequence Data
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Mutation, Missense*
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Point Mutation*
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Polycythemia / congenital*
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Polycythemia / genetics
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Procollagen-Proline Dioxygenase / metabolism
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Protein Interaction Mapping
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Sequence Alignment
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Sequence Homology, Amino Acid
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Signal Transduction / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Erythropoietin
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endothelial PAS domain-containing protein 1
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EGLN1 protein, human
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Procollagen-Proline Dioxygenase
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human
Supplementary concepts
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Polycythemia, primary familial and congenital