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    HFE homeostatic iron regulator [ Homo sapiens (human) ]

    Gene ID: 3077, updated on 19-Jul-2021

    Summary

    Official Symbol
    HFEprovided by HGNC
    Official Full Name
    homeostatic iron regulatorprovided by HGNC
    Primary source
    HGNC:HGNC:4886
    See related
    Ensembl:ENSG00000010704 MIM:613609
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    HH; HFE1; HLA-H; MVCD7; TFQTL2
    Summary
    The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. At least nine alternatively spliced variants have been described for this gene. Additional variants have been found but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]
    Expression
    Ubiquitous expression in thyroid (RPKM 5.0), gall bladder (RPKM 4.6) and 24 other tissues See more
    Orthologs
    NEW
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    Try the new Transcript table

    Genomic context

    See HFE in Genome Data Viewer
    Location:
    6p22.2
    Exon count:
    7
    Annotation release Status Assembly Chr Location
    109.20210514 current GRCh38.p13 (GCF_000001405.39) 6 NC_000006.12 (26087347..26098343)
    105.20201022 previous assembly GRCh37.p13 (GCF_000001405.25) 6 NC_000006.11 (26087657..26098571)

    Chromosome 6 - NC_000006.12Genomic Context describing neighboring genes Neighboring gene H3 clustered histone 3 Neighboring gene H1.2 linker histone, cluster member Neighboring gene HFE antisense RNA 1 Neighboring gene H4 clustered histone 3 Neighboring gene H1.6 linker histone, cluster member

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    Phenotypes

    Associated conditions

    Description Tests
    A genome-wide association study of red blood cell traits using the electronic medical record.
    GeneReviews: Not available
    A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.
    GeneReviews: Not available
    Alzheimer disease
    MedGen: C0002395 OMIM: 104300 GeneReviews: Alzheimer Disease Overview
    Compare labs
    Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.
    GeneReviews: Not available
    Biological, clinical and population relevance of 95 loci for blood lipids.
    GeneReviews: Not available
    Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
    GeneReviews: Not available
    Common variants in TMPRSS6 are associated with iron status and erythrocyte volume.
    GeneReviews: Not available
    Discovery and refinement of loci associated with lipid levels.
    GeneReviews: Not available
    Familial porphyria cutanea tarda Compare labs
    Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.
    GeneReviews: Not available
    Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
    GeneReviews: Not available
    Genome-wide admixture and association study of serum iron, ferritin, transferrin saturation and total iron binding capacity in African Americans.
    GeneReviews: Not available
    Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.
    GeneReviews: Not available
    Genome-wide association study identifies genetic loci associated with iron deficiency.
    GeneReviews: Not available
    Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
    GeneReviews: Not available
    Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.
    GeneReviews: Not available
    Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels.
    GeneReviews: Not available
    Genome-wide association study of hematological and biochemical traits in a Japanese population.
    GeneReviews: Not available
    GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children.
    GeneReviews: Not available
    Hemochromatosis type 1
    MedGen: C3469186 OMIM: 235200 GeneReviews: HFE Hemochromatosis
    Compare labs
    Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.
    GeneReviews: Not available
    Microvascular complications of diabetes 7
    MedGen: C2673520 OMIM: 612635 GeneReviews: Not available
    Compare labs
    Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.
    GeneReviews: Not available
    Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels.
    GeneReviews: Not available
    Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.
    GeneReviews: Not available
    Sequence variants in three loci influence monocyte counts and erythrocyte volume.
    GeneReviews: Not available
    Seventy-five genetic loci influencing the human red blood cell.
    GeneReviews: Not available
    Transferrin serum level quantitative trait locus 2
    MedGen: C3280096 OMIM: 614193 GeneReviews: Not available
    Compare labs
    Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels.
    GeneReviews: Not available
    Variegate porphyria
    MedGen: C0162532 OMIM: 176200 GeneReviews: Variegate Porphyria
    Compare labs

    HIV-1 interactions

    Protein interactions

    Protein Gene Interaction Pubs
    Nef nef Myristoylation of HIV-1 Nef at position 2 and the PxxP proline-rich motif of Nef at positions 62-65 are required for Nef-induced downregulation of HFE; amino acid residue Y282 in HFE is involved in the downregulation by Nef PubMed
    nef HIV-1 Nef downregulates the macrophage-expressed MHC 1b protein HFE by rerouting HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Homology

    Clone Names

    • MGC103790, MGC:150812, dJ221C16.10.1, IMAGE:40125754

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables beta-2-microglobulin binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables co-receptor binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    NOT enables peptide antigen binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    NOT enables peptide antigen binding IKR
    Inferred from Key Residues
    more info
    PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables signaling receptor binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables transferrin receptor binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    enables transferrin receptor binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    Process Evidence Code Pubs
    involved_in BMP signaling pathway IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in acute-phase response IEA
    Inferred from Electronic Annotation
    more info
     
    NOT involved_in antigen processing and presentation IC
    Inferred by Curator
    more info
    PubMed 
    NOT involved_in antigen processing and presentation of peptide antigen via MHC class I IKR
    Inferred from Key Residues
    more info
    PubMed 
    involved_in cellular iron ion homeostasis IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in cellular response to iron ion IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in cellular response to iron ion starvation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in female pregnancy IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in hormone biosynthetic process IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in iron ion homeostasis IC
    Inferred by Curator
    more info
    PubMed 
    involved_in iron ion homeostasis IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in iron ion import across plasma membrane IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in liver regeneration IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in multicellular organismal iron ion homeostasis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of CD8-positive, alpha-beta T cell activation IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in negative regulation of T cell antigen processing and presentation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of T cell cytokine production IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in negative regulation of proteasomal ubiquitin-dependent protein catabolic process IC
    Inferred by Curator
    more info
    PubMed 
    involved_in negative regulation of receptor binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of signaling receptor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of ubiquitin-dependent protein catabolic process IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of ferrous iron binding IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in positive regulation of gene expression ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of pathway-restricted SMAD protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of peptide hormone secretion IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in positive regulation of protein binding IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in positive regulation of receptor binding IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in positive regulation of receptor-mediated endocytosis IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in positive regulation of signaling receptor activity IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in positive regulation of transferrin receptor binding IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in protein-containing complex assembly TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in regulation of iron ion transport IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in regulation of iron ion transport IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in regulation of protein localization to cell surface IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in response to iron ion IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in response to iron ion starvation IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    Component Evidence Code Pubs
    part_of HFE-transferrin receptor complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    NOT part_of MHC class I protein complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    NOT part_of MHC class I protein complex IKR
    Inferred from Key Residues
    more info
    PubMed 
    located_in apical part of cell IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in basal part of cell IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in cytoplasmic vesicle IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in early endosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    is_active_in external side of plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    located_in external side of plasma membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    is_active_in extracellular space IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    located_in extracellular space IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in integral component of plasma membrane TAS
    Traceable Author Statement
    more info
    PubMed 
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
     
    located_in perinuclear region of cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
     
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
     
    located_in recycling endosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in terminal web IEA
    Inferred from Electronic Annotation
    more info
     

    General protein information

    Preferred Names
    hereditary hemochromatosis protein
    Names
    MHC class I-like protein HFE
    hereditary hemochromatosis protein HLA-H
    high Fe

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_008720.2 RefSeqGene

      Range
      5001..12961
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_748

    mRNA and Protein(s)

    1. NM_000410.4NP_000401.1  hereditary hemochromatosis protein isoform 1 precursor

      See identical proteins and their annotated locations for NP_000401.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform.
      Source sequence(s)
      U91328
      Consensus CDS
      CCDS4578.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000417404.1, ENST00000357618.10
      Conserved Domains (2) summary
      cd07698
      Location:206298
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27202
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    2. NM_001300749.2NP_001287678.1  hereditary hemochromatosis protein isoform 12 precursor

      Status: REVIEWED

      Description
      Transcript Variant: This variant (12) uses an alternate splice acceptor site at its 3'-terminal exon, compared to variant 1. This variant encodes isoform 12 which has a shorter and distinct C-terminus, compared to isoform 1.
      Source sequence(s)
      AJ249337, AJ298840, AK300933, BC117201
      Consensus CDS
      CCDS75412.1
      UniProtKB/Swiss-Prot
      Q30201
      UniProtKB/TrEMBL
      B4DV50, F8W7W8
      Related
      ENSP00000311698.6, ENST00000309234.10
      Conserved Domains (2) summary
      cd07698
      Location:206298
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27202
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    3. NM_001384164.1NP_001371093.1  hereditary hemochromatosis protein isoform 13 precursor

      Status: REVIEWED

      Source sequence(s)
      U91328
      Conserved Domains (2) summary
      cd21021
      Location:204297
      IgC1_MHC_Ib_HLA-H; Class Ib major histocompatibility complex (MHC) immunoglobulin domain of human leukocyte antigen H; member of the C1-set of Ig superfamily (IgSF) domains
      cl08246
      Location:27202
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    4. NM_139003.3NP_620572.1  hereditary hemochromatosis protein isoform 3 precursor

      See identical proteins and their annotated locations for NP_620572.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks an internal in-frame segment of the coding region, as compared to variant 1, resulting in a shorter protein (isoform 3).
      Source sequence(s)
      AF149804, AJ249335, U91328
      Consensus CDS
      CCDS47386.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000337819.8, ENST00000336625.12
      Conserved Domains (2) summary
      cd07698
      Location:110192
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27113
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    5. NM_139004.3NP_620573.1  hereditary hemochromatosis protein isoform 4 precursor

      See identical proteins and their annotated locations for NP_620573.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) lacks an internal in-frame segment of the coding region, compared to variant 1, resulting in a shorter protein (isoform 4).
      Source sequence(s)
      AJ249337, U91328
      Consensus CDS
      CCDS4579.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000313776.7, ENST00000317896.11
      Conserved Domains (2) summary
      cd07698
      Location:114206
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27113
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    6. NM_139006.3NP_620575.1  hereditary hemochromatosis protein isoform 6 precursor

      See identical proteins and their annotated locations for NP_620575.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) lacks an internal in-frame segment of the coding region, as compared to variant 1, resulting in a shorter protein (isoform 6).
      Source sequence(s)
      AF079407, U91328
      Consensus CDS
      CCDS54974.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000420802.1, ENST00000461397.5
      Conserved Domains (2) summary
      cd07698
      Location:207284
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27202
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    7. NM_139007.3NP_620576.1  hereditary hemochromatosis protein isoform 7 precursor

      See identical proteins and their annotated locations for NP_620576.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (7) lacks an internal in-frame segment of the coding region, as compared to variant 1, resulting in a shorter protein isoform (7).
      Source sequence(s)
      AJ249336, U91328
      Consensus CDS
      CCDS4580.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000259699.6, ENST00000349999.8
      Conserved Domains (2) summary
      cd07698
      Location:118210
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27114
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    8. NM_139008.3NP_620577.1  hereditary hemochromatosis protein isoform 8 precursor

      See identical proteins and their annotated locations for NP_620577.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (8) lacks two internal in-frame segments of the coding region, as compared to variant 1, resulting in a shorter protein (isoform 8).
      Source sequence(s)
      AF079409, U91328
      Consensus CDS
      CCDS54975.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000420559.1, ENST00000488199.5
      Conserved Domains (2) summary
      cd07698
      Location:119196
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:27114
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    9. NM_139009.3NP_620578.1  hereditary hemochromatosis protein isoform 9 precursor

      See identical proteins and their annotated locations for NP_620578.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (9) lacks an internal in-frame segment of the coding region through the use of an alternate splice acceptor site, as compared to variant 1, resulting in a shorter protein (isoform 9).
      Source sequence(s)
      AJ249335, U91328
      Consensus CDS
      CCDS47387.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000380217.3, ENST00000397022.7
      Conserved Domains (2) summary
      cd07698
      Location:183275
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
      cl08246
      Location:23179
      MHC_I; Class I Histocompatibility antigen, domains alpha 1 and 2
    10. NM_139010.3NP_620579.1  hereditary hemochromatosis protein isoform 10 precursor

      See identical proteins and their annotated locations for NP_620579.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (10) lacks an internal in-frame segment of the coding region, as compared to variant 1, resulting in a shorter protein (isoform 10).
      Source sequence(s)
      AJ250635, U91328
      Consensus CDS
      CCDS4581.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000312342.5, ENST00000353147.9
      Conserved Domains (1) summary
      cd07698
      Location:27118
      IgC_MHC_I_alpha3; Class I major histocompatibility complex (MHC) alpha chain immunoglobulin domain
    11. NM_139011.3NP_620580.1  hereditary hemochromatosis protein isoform 11 precursor

      See identical proteins and their annotated locations for NP_620580.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (11) lacks a large internal part of the coding region but the reading frame is maintained, as compared to variant 1. The protein encoded is the shortest isoform (11).
      Source sequence(s)
      AJ249338, U91328
      Consensus CDS
      CCDS4582.1
      UniProtKB/Swiss-Prot
      Q30201
      Related
      ENSP00000315936.4, ENST00000352392.8

    RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20210514

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p13 Primary Assembly

    Genomic

    1. NC_000006.12 Reference GRCh38.p13 Primary Assembly

      Range
      26087347..26098343
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    RNA

    1. XR_241893.4 RNA Sequence

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_139002.2: Suppressed sequence

      Description
      NM_139002.2: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.
    2. NM_139005.2: Suppressed sequence

      Description
      NM_139005.2: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.
    Support Center