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HFE (hemochromatosis)

Identity

Other namesHFE1
HH
HLA-H
MGC103790
dJ221C16.10.1
HGNC (Hugo) HFE
LocusID (NCBI) 3077
Location 6p22.2
Location_base_pair Starts at 26087509 and ends at 26095469 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Note History and Nomenclature: The HFE gene was discovered in 1996 by Feder et al after a long search in the vicinity of the HLA-A locus. It is around 5 Mb telomeric to HLA-A in physical distance but genetic distance is less than 1 cM. Unfortunately, it was originally named HLA-H as the HLA class I-like hemochromatosis gene but there was already a gene called HLA-H. Thus, the hemochromatosis gene should not be called HLA-H. According to nomenclature conventions, the gene is called HFE and the protein product is HFE. There is no pseudogene derived from HFE.
 
Description HFE encompasses 9,609 bp of DNA on chromosome 6 (6p22.1) between 26,195,426 - 26,205,034 bp from pter within the extended HLA class I region. Histone genes populate either side of the HFE gene. It is an HLA class-I-like molecule but is not involved in antigen presentation or immune response.
Transcription HFE has at least nine alternatively spliced forms. The full-length transcript contains six exons, however, the number of exons can be as few as three (see Figure).

Protein

Description HFE is a beta2-microglobulin-associated membrane protein similar to HLA class I molecules. It consists of an a-chain encoded by HFE and beta2-microglobulin as the b-chain.
Expression Expressed in a wide range of cell types and tissues including lymphocytes and placenta.
Localisation HFE is a cell surface membrane protein.
Function HFE is primarily involved in iron homeostasis. Initially it was thought that it directly regulated intestinal iron absorption. It is now believed that functional HFE is required for normal regulation of hepcidin synthesis, which is the main regulator of iron metabolism. Mutations of HFE result in iron overload.

Mutations

Note Two missense mutations C282Y (rs1800562) and H63D (rs1799945) are relatively common. C282Y is most common in Northern European populations and H63D has a global distribution. Whereas the prevalence of these mutations is high, the clinical penetrance of the disease they cause is low.
  • There is no nonsense mutation described in HFE.
  • Missense mutations are involved in pathogenesis of iron overload.
  • HFE is not involved in any known translocations.
  • Hfe knockout mice are viable and develop iron overload.
  • Implicated in

    Entity Iron Overload
    Disease Mutations in HFE increase body iron levels and homozygosity or compound heterozygosity may cause iron overload. The penetrance is low. Dietary iron intake, alcohol consumption and blood loss are environmental modifiers. The importance of iron overload is that it increases the risk for cancer development presumably due to its potential to cause oxidative DNA damage.
      
    Entity Hereditary Hemochromatosis
    Disease Hereditary hemochromatosis (HH; OMIM 235200) is a recessive iron storage disorder resulting from defects in HFE. HH (type 1) is the most common autosomal recessive disease in Caucasians adults. Most patients (about 90%) are homozygous for the C282Y mutation and another 4% are compound heterozygotes (C282Y, H63D). Different forms of non-HFE hemochromatosis are caused by other iron-related genes: type 2 (mutations in HFE2), type 3 (mutations in TFR2) and type 4 (mutations in SLC40A1 'ferroportin'). HH is characterized by abnormal intestinal iron absorption and elevated total body iron levels. Iron overload results in clinical complications including cirrhosis, cardiopathy, endocrine dysfunctions including diabetes, arthropathy and susceptibility to liver cancer. The penetrance is higher in males due to regular blood loss in premenopausal women. Disease complications can be prevented by regular phlebotomy. The effect of HFE on disease phenotype can be modified by other iron-related genes including hepcidin (HAMP), transferrin (TF), transferrin receptor (TFRC), haptoglobin (HP) and ceruloplasmin (CP).
      
    Entity Porphyria variegata
    Disease Defects in HFE also cause porphyria variegata (OMIM 176200). Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. Porphyria variegata is the prevalent form in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. Iron overload is the hallmark of the disease.
      
    Entity Leukemias
    Disease HFE mutations do not cause cancer and HFE mutations are not detected preferentially in cancer cells as somatic mutations. Both C282Y and H63D mutations, however, have been implicated in susceptibility to leukemias and other cancers. In South Wales (U.K.), C282Y mutation is associated with increased risk to childhood acute lymphoblastic leukemia in boys only. This association has not been noted in other studies in Finland, Spain and Mexico. In Italy, adult leukemia shows an association with H63D mutation.
      
    Entity Breast Cancer
    Disease Studies in USA, Russia and Turkey have found risk associations with HFE mutations C282Y and/or H63D with breast cancer. A Swedish study found a risk association only in women homozygous for the TFRC variant S142G.
      
    Entity Other cancers
    Disease In Sweden, combination of HFE mutation C282Y and/or H63D and homozygosity for the TFRC variant S142G increase susceptibility to multiple myeloma, hepatocellular carcinoma and colon cancer (besides breast cancer). An interaction of HFE mutations with dietary intake of excessive iron also increases the risk for colorectal cancer. Various studies have reported increased frequency of HFE mutations in hepatocellular carcinoma secondary to hepatic iron overload but not in HCV-induced hepatocellular carcinoma. There appears to be an interaction between HFE and alcohol in the induction of iron overload, cirrhosis and subsequent hepatocellular carcinoma. For each genetic association report between HFE and any cancer, there is also one or more negative association report. It appears that only large and comprehensive studies taking into account gene x gene and gene x environment interactions may conclude this issue.
      

    External links

    Nomenclature
    HGNC (Hugo)HFE   4886
    Cards
    AtlasHFEID44099ch6p22
    Entrez_Gene (NCBI)HFE  3077  hemochromatosis
    GeneCards (Weizmann)HFE
    Ensembl (Hinxton)ENSG00000010704 [Gene_View]  chr6:26087509-26095469 [Contig_View]  HFE [Vega]
    AceView (NCBI)HFE
    Genatlas (Paris)HFE
    WikiGenes3077
    SOURCE (Princeton)NM_000410 NM_139002 NM_139003 NM_139004 NM_139005 NM_139006 NM_139007 NM_139008 NM_139009 NM_139010 NM_139011
    Genomic and cartography
    GoldenPath (UCSC)HFE  -  6p22.2   chr6:26087509-26095469 +  6p21.3   [Description]    (hg19-Feb_2009)
    EnsemblHFE - 6p21.3 [CytoView]
    Mapping of homologs : NCBIHFE [Mapview]
    OMIM104300   176100   176200   190000   235200   612635   613609   614193   
    Gene and transcription
    Genbank (Entrez)AF079407 AF079408 AF079409 AF109385 AF115264
    RefSeq transcript (Entrez)NM_000410 NM_139002 NM_139003 NM_139004 NM_139005 NM_139006 NM_139007 NM_139008 NM_139009 NM_139010 NM_139011
    RefSeq genomic (Entrez)AC_000138 NC_000006 NC_018917 NG_008720 NT_007592 NW_001838974 NW_004929326
    Consensus coding sequences : CCDS (NCBI)HFE
    Cluster EST : UnigeneHs.233325 [ NCBI ]
    CGAP (NCI)Hs.233325
    Alternative Splicing : Fast-db (Paris)GSHG0025489
    Alternative Splicing GalleryENSG00000010704
    Gene ExpressionHFE [ NCBI-GEO ]     HFE [ SEEK ]   HFE [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ30201 (Uniprot)
    NextProtQ30201  [Medical]
    With graphics : InterProQ30201
    Splice isoforms : SwissVarQ30201 (Swissvar)
    Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    IG_MHC (PS00290)   
    Domains : Interpro (EBI)Ig-like_dom    Ig-like_fold    Ig/MHC_CS    Ig_C1-set    MHC_I-like_Ag-recog    MHC_I/II-like_Ag-recog    MHC_I_a    MHC_I_a_a1/a2   
    Related proteins : CluSTrQ30201
    Domain families : Pfam (Sanger)C1-set (PF07654)    MHC_I (PF00129)   
    Domain families : Pfam (NCBI)pfam07654    pfam00129   
    Domain families : Smart (EMBL)IGc1 (SM00407)  
    DMDM Disease mutations3077
    Blocks (Seattle)Q30201
    PDB (SRS)1A6Z    1C42    1DE4   
    PDB (PDBSum)1A6Z    1C42    1DE4   
    PDB (IMB)1A6Z    1C42    1DE4   
    PDB (RSDB)1A6Z    1C42    1DE4   
    Human Protein AtlasENSG00000010704
    Peptide AtlasQ30201
    HPRD01993
    IPIIPI00029419   IPI00215955   IPI00218211   IPI00218212   IPI00218213   IPI00218215   IPI00294375   IPI00218218   IPI00218221   IPI00478396   IPI00387143   IPI00872464   IPI00472016   IPI00387151   IPI00816163   IPI00064823   IPI00944973   IPI00946002   IPI00945116   
    Protein Interaction databases
    DIP (DOE-UCLA)Q30201
    IntAct (EBI)Q30201
    FunCoupENSG00000010704
    BioGRIDHFE
    InParanoidQ30201
    Interologous Interaction database Q30201
    IntegromeDBHFE
    STRING (EMBL)HFE
    Ontologies - Pathways
    Ontology : AmiGOpositive regulation of T cell mediated cytotoxicity  antigen processing and presentation of peptide antigen via MHC class I  antigen binding  receptor binding  protein binding  early endosome  plasma membrane  integral to plasma membrane  protein complex assembly  cellular iron ion homeostasis  immune response  female pregnancy  cellular response to iron ion starvation  antigen processing and presentation  cytoplasmic vesicle  hormone biosynthetic process  peptide antigen binding  MHC class I protein complex  apical part of cell  basal part of cell  perinuclear region of cytoplasm  recycling endosome  multicellular organismal iron ion homeostasis  iron ion import into cell  
    Ontology : EGO-EBIpositive regulation of T cell mediated cytotoxicity  antigen processing and presentation of peptide antigen via MHC class I  antigen binding  receptor binding  protein binding  early endosome  plasma membrane  integral to plasma membrane  protein complex assembly  cellular iron ion homeostasis  immune response  female pregnancy  cellular response to iron ion starvation  antigen processing and presentation  cytoplasmic vesicle  hormone biosynthetic process  peptide antigen binding  MHC class I protein complex  apical part of cell  basal part of cell  perinuclear region of cytoplasm  recycling endosome  multicellular organismal iron ion homeostasis  iron ion import into cell  
    REACTOMEHFE
    Protein Interaction DatabaseHFE
    Wikipedia pathwaysHFE
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)HFE
    SNP (GeneSNP Utah)HFE
    SNP : HGBaseHFE
    Genetic variants : HAPMAPHFE
    1000_GenomesHFE 
    ICGC programENSG00000010704 
    Somatic Mutations in Cancer : COSMICHFE 
    CONAN: Copy Number AnalysisHFE 
    Mutations and Diseases : HGMDHFE
    OMIM104300    176100    176200    190000    235200    612635    613609    614193   
    GENETestsHFE
    Disease Genetic AssociationHFE
    Huge Navigator HFE [HugePedia]  HFE [HugeCancerGEM]
    Genomic VariantsHFE  HFE [DGVbeta]
    Exome VariantHFE
    dbVarHFE
    ClinVarHFE
    snp3D : Map Gene to Disease3077
    General knowledge
    Homologs : HomoloGeneHFE
    Homology/Alignments : Family Browser (UCSC)HFE
    Phylogenetic Trees/Animal Genes : TreeFamHFE
    Chemical/Protein Interactions : CTD3077
    Chemical/Pharm GKB GenePA29263
    Clinical trialHFE
    Cancer Resource (Charite)ENSG00000010704
    Other databases
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineHFE
    iHOPHFE

    Bibliography

    A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK
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    Putting a hold on HLA-H'. The WHO Nomenclature Committee for Factors of the HLA System.
    Bodmer JG, Parham P, Albert ED, Marsh SG
    Nature genetics. 1997 ; 15 (3) : 234-235.
    PMID 9054933
     
    The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression.
    Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, Prass CE, Starnes SM, Wolff RK, Parkkila S, Sly WS, Schatzman RC
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    PMID 9162021
     
    The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
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    Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (4) : 1472-1477.
    PMID 9465039
     
    Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
    Lebrˆ„n JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ
    Cell. 1998 ; 93 (1) : 111-123.
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    Interaction between haemochromatosis and transferrin receptor genes in multiple myeloma.
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    HFE gene knockout produces mouse model of hereditary hemochromatosis.
    Zhou XY, Tomatsu S, Fleming RE, Parkkila S, Waheed A, Jiang J, Fei Y, Brunt EM, Ruddy DA, Prass CE, Schatzman RC, O'Neill R, Britton RS, Bacon BR, Sly WS
    Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (5) : 2492-2497.
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    Interaction between haemochromatosis and transferrin receptor genes in different neoplastic disorders.
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    PMID 10383894
     
    The C282Y mutation of HFE is another male-specific risk factor for childhood acute lymphoblastic leukemia.
    Dorak MT, Burnett AK, Worwood M, Sproul AM, Gibson BE
    Blood. 1999 ; 94 (11) : page 3957.
    PMID 10627122
     
    Prevalence of hemochromatosis related HFE gene mutations in patients with acute myeloid leukemia.
    Gimferrer E, Nomdedeu J, Gich I, Barcelˆ„ MJ, Baiget M
    Leukemia research. 1999 ; 23 (6) : 597-598.
    PMID 10374855
     
    Interaction between haemochromatosis and transferrin receptor genes in hepatocellular carcinoma.
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    Oncology. 2000 ; 59 (4) : 317-322.
    PMID 11096344
     
    Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor.
    Bennett MJ, Lebrˆ„n JA, Bjorkman PJ
    Nature. 2000 ; 403 (6765) : 46-53.
    PMID 10638746
     
    HFE--a novel nonclassical class I molecule that is involved in iron metabolism.
    Ehrlich R, Lemonnier FA
    Immunity. 2000 ; 13 (5) : 585-588.
    PMID 11114371
     
    Iron transport in a lymphoid cell line with the hemochromatosis C282Y mutation.
    Chitambar CR, Wereley JP
    Blood. 2001 ; 97 (9) : 2734-2740.
    PMID 11313265
     
    HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology.
    Hanson EH, Imperatore G, Burke W
    American journal of epidemiology. 2001 ; 154 (3) : 193-206.
    PMID 11479183
     
    High frequency of the H63D mutation of the hemochromatosis gene (HFE) in malignant gliomas.
    Martinez di Montemuros F, Tavazzi D, Salsano E, Piepoli T, Pollo B, Fiorelli G, Finocchiaro G
    Neurology. 2001 ; 57 (7) : page 1342.
    PMID 11591868
     
    Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders.
    Hannuksela J, Savolainen ER, Koistinen P, Parkkila S
    Haematologica. 2002 ; 87 (2) : 131-135.
    PMID 11836162
     
    Sequence variation and haplotype structure at the human HFE locus.
    Toomajian C, Kreitman M
    Genetics. 2002 ; 161 (4) : 1609-1623.
    PMID 12196404
     
    Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.
    Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH, Subramaniam VN, Powell LW, Anderson GJ, Ramm GA
    Lancet. 2003 ; 361 (9358) : 669-673.
    PMID 12606179
     
    Iron overload and its association with cancer risk in humans: evidence for iron as a carcinogenic metal.
    Huang X
    Mutation research. 2003 ; 533 (1-2) : 153-171.
    PMID 14643418
     
    Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer.
    Shaheen NJ, Silverman LM, Keku T, Lawrence LB, Rohlfs EM, Martin CF, Galanko J, Sandler RS
    Journal of the National Cancer Institute. 2003 ; 95 (2) : 154-159.
    PMID 12529348
     
    Oxidative damage in colon and mammary tissue of the HFE-knockout mouse.
    Stevens RG, Morris JE, Cordis GA, Anderson LE, Rosenberg DW, Sasser LB
    Free radical biology & medicine. 2003 ; 34 (9) : 1212-1216.
    PMID 12706501
     
    Heterozygosity for the Cys282Tyr mutation in the HFE gene and the risk of colorectal cancer (Netherlands).
    van der A DL, van der Hel O, Roest M, van der Schouw YT, van Gils CH, Marx JJ, van Noord PA, Peeters PH
    Cancer causes & control : CCC. 2003 ; 14 (6) : 541-545.
    PMID 12948285
     
    Iron overload in acute myeloid leukemia patients is not related to HFE and TFR2 gene mutations.
    Veneri D, Franchini M, Zanetti F, Krampera M, de Matteis G, Pizzolo G
    Haematologica. 2003 ; 88 (9) : 1069-1070.
    PMID 12969816
     
    HFE C282Y and H63D in adults with malignancies in a community medical oncology practice.
    Barton JC, Bertoli LF, Acton RT
    BMC cancer. 2004 ; 4 : page 6.
    PMID 15018631
     
    HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype.
    Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C
    Blood. 2004 ; 103 (7) : 2835-2840.
    PMID 14670915
     
    Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer.
    Kallianpur AR, Hall LD, Yadav M, Christman BW, Dittus RS, Haines JL, Parl FF, Summar ML
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2004 ; 13 (2) : 205-212.
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    Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer.
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    PMID 15894659
     
    Hemochromatosis gene mutations, body iron stores, dietary iron, and risk of colorectal adenoma in women.
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    Journal of the National Cancer Institute. 2005 ; 97 (12) : 917-926.
    PMID 15956653
     
    HFE gene mutations in susceptibility to childhood leukemia: HuGE review.
    Dorak MT, Burnett AK, Worwood M
    Genetics in medicine : official journal of the American College of Medical Genetics. 2005 ; 7 (3) : 159-168.
    PMID 15775751
     
    Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.
    Robinson JP, Johnson VL, Rogers PA, Houlston RS, Maher ER, Bishop DT, Evans DG, Thomas HJ, Tomlinson IP, Silver AR
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    PMID 15941956
     
    Analysis of HFE and TFR2 gene mutations in patients with acute leukemia.
    Veneri D, Franchini M, Krampera M, de Matteis G, Solero P, Pizzolo G
    Leukemia research. 2005 ; 29 (6) : 661-664.
    PMID 15863206
     
    HFE H63D variant and leukemia susceptibility.
    Dorak MT
    Leukemia & lymphoma. 2006 ; 47 (11) : 2269-2270.
    PMID 17107894
     
    HFE H63D mutation frequency shows an increase in Turkish women with breast cancer.
    Gunel-Ozcan A, Alyilmaz-Bekmez S, Guler EN, Guc D
    BMC cancer. 2006 ; 6 : page 37.
    PMID 16503999
     
    The significance of the hemochromatosis genetic variants in multiple myeloma in comparison to that of myelodysplastic syndrome.
    Vˆ°rkonyi J, Demeter J, Tordai A, Andrikovics H
    Annals of hematology. 2006 ; 85 (12) : 869-871.
    PMID 17001480
     
    HFE gene mutations in patients with acute leukemia.
    Viola A, Pagano L, Laudati D, D'Elia R, D'Amico MR, Ammirabile M, Palmieri S, Prossomariti L, Ferrara F
    Leukemia & lymphoma. 2006 ; 47 (11) : 2331-2334.
    PMID 17107905
     
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    Contributor(s)

    Written03-2008M Tevfik Dorak
    Genomic Immunoepidemiology Laboratory, HUMIGEN LLC, The Institute for Genetic Immunology, Hamilton, NJ 08690-3303, USA

    Citation

    This paper should be referenced as such :
    Dorak MT . HFE (hemochromatosis). Atlas Genet Cytogenet Oncol Haematol. March 2008 .
    URL : http://AtlasGeneticsOncology.org/Genes/HFEID44099ch6p22.html

    The various updated versions of this paper are referenced and archived by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/44377/1/03-2008-HFEID44099ch6p22.pdf   [ Bibliographic record ]

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    indexed on : Fri Apr 18 17:20:53 CEST 2014

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