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HFE (hemochromatosis)

Written2008-03M Tevfik Dorak
Genomic Immunoepidemiology Laboratory, HUMIGEN LLC, The Institute for Genetic Immunology, Hamilton, NJ 08690-3303, USA

(Note : for Links provided by Atlas : click)


Alias (NCBI)HFE1
HGNC Alias symbHLA-H
HGNC Alias namehigh Fe
HGNC Previous namehemochromatosis
LocusID (NCBI) 3077
Atlas_Id 44099
Location 6p22.2  [Link to chromosome band 6p22]
Location_base_pair Starts at 26087429 and ends at 26098342 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping HFE.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


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).


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 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.


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.


    Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer.
    Abraham BK, Justenhoven C, Pesch B, Harth V, Weirich G, Baisch C, Rabstein S, Ko YD, Brüning T, Fischer HP, Haas S, Brod S, Oberkanins C, Hamann U, GENICA Network, Brauch H
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005 ; 14 (5) : 1102-1107.
    PMID 15894659
    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
    Interaction between haemochromatosis and transferrin receptor genes in hepatocellular carcinoma.
    Beckman LE, Hägerstrand I, Stenling R, Van Landeghem GF, Beckman L
    Oncology. 2000 ; 59 (4) : 317-322.
    PMID 11096344
    Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor.
    Bennett MJ, Lebrón JA, Bjorkman PJ
    Nature. 2000 ; 403 (6765) : 46-53.
    PMID 10638746
    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
    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
    Hemochromatosis gene mutations, body iron stores, dietary iron, and risk of colorectal adenoma in women.
    Chan AT, Ma J, Tranah GJ, Giovannucci EL, Rifai N, Hunter DJ, Fuchs CS
    Journal of the National Cancer Institute. 2005 ; 97 (12) : 917-926.
    PMID 15956653
    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 H63D variant and leukemia susceptibility.
    Dorak MT
    Leukemia & lymphoma. 2006 ; 47 (11) : 2269-2270.
    PMID 17107894
    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
    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
    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
    Nature genetics. 1996 ; 13 (4) : 399-408.
    PMID 8696333
    The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
    Feder JN, Penny DM, Irrinki A, Lee VK, Lebrón JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC
    Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (4) : 1472-1477.
    PMID 9465039
    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
    The Journal of biological chemistry. 1997 ; 272 (22) : 14025-14028.
    PMID 9162021
    Prevalence of hemochromatosis related HFE gene mutations in patients with acute myeloid leukemia.
    Gimferrer E, Nomdedeu J, Gich I, Barceló MJ, Baiget M
    Leukemia research. 1999 ; 23 (6) : 597-598.
    PMID 10374855
    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
    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
    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
    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
    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.
    PMID 14973098
    Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
    Lebrón JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ
    Cell. 1998 ; 93 (1) : 111-123.
    PMID 9546397
    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
    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
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005 ; 14 (6) : 1460-1463.
    PMID 15941956
    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
    Sequence variation and haplotype structure at the human HFE locus.
    Toomajian C, Kreitman M
    Genetics. 2002 ; 161 (4) : 1609-1623.
    PMID 12196404
    The significance of the hemochromatosis genetic variants in multiple myeloma in comparison to that of myelodysplastic syndrome.
    V´rkonyi J, Demeter J, Tordai A, Andrikovics H
    Annals of hematology. 2006 ; 85 (12) : 869-871.
    PMID 17001480
    Interaction between haemochromatosis and transferrin receptor genes in multiple myeloma.
    Van Landeghem GF, Beckman LE, Wahlin A, Markevärn B, Beckman L
    Lancet. 1998 ; 352 (9136) : 1285-1286.
    PMID 9788468
    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 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
    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.
    PMID 9482913
    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


    This paper should be referenced as such :
    Dorak, MT
    HFE (hemochromatosis)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):11-14.
    Free journal version : [ pdf ]   [ DOI ]

    External links

    HGNC (Hugo)HFE   4886
    LRG (Locus Reference Genomic)LRG_748
    Entrez_Gene (NCBI)HFE    homeostatic iron regulator
    AliasesHFE1; HH; HLA-H; MVCD7; 
    GeneCards (Weizmann)HFE
    Ensembl hg19 (Hinxton)ENSG00000010704 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000010704 [Gene_View]  ENSG00000010704 [Sequence]  chr6:26087429-26098342 [Contig_View]  HFE [Vega]
    ICGC DataPortalENSG00000010704
    TCGA cBioPortalHFE
    AceView (NCBI)HFE
    Genatlas (Paris)HFE
    SOURCE (Princeton)HFE
    Genetics Home Reference (NIH)HFE
    Genomic and cartography
    GoldenPath hg38 (UCSC)HFE  -     chr6:26087429-26098342 +  6p22.2   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)HFE  -     6p22.2   [Description]    (hg19-Feb_2009)
    GoldenPathHFE - 6p22.2 [CytoView hg19]  HFE - 6p22.2 [CytoView hg38]
    Genome Data Viewer NCBIHFE [Mapview hg19]  
    OMIM104300   176100   176200   235200   612635   613609   614193   
    Gene and transcription
    Genbank (Entrez)AF079407 AF079408 AF079409 AF109385 AF115264
    RefSeq transcript (Entrez)NM_000410 NM_001300749 NM_001384164 NM_139002 NM_139003 NM_139004 NM_139005 NM_139006 NM_139007 NM_139008 NM_139009 NM_139010 NM_139011
    Consensus coding sequences : CCDS (NCBI)HFE
    Gene ExpressionHFE [ NCBI-GEO ]   HFE [ EBI - ARRAY_EXPRESS ]   HFE [ SEEK ]   HFE [ MEM ]
    Gene Expression Viewer (FireBrowse)HFE [ Firebrowse - Broad ]
    GenevisibleExpression of HFE in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)3077
    GTEX Portal (Tissue expression)HFE
    Human Protein AtlasENSG00000010704-HFE [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    Domain families : Pfam (Sanger)
    Domain families : Pfam (NCBI)
    Conserved Domain (NCBI)HFE
    Human Protein Atlas [tissue]ENSG00000010704-HFE [tissue]
    Protein Interaction databases
    Ontologies - Pathways
    PubMed499 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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