HFE (hemochromatosis)

2008-03-01   M Tevfik Dorak 

Genomic Immunoepidemiology Laboratory, HUMIGEN LLC, The Institute for Genetic Immunology, Hamilton, NJ 08690-3303, USA





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.
Atlas Image


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.


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).



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.


Expressed in a wide range of cell types and tissues including lymphocytes and placenta.


HFE is a cell surface membrane protein.


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.



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 name
    Iron Overload
    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 name
    Hereditary Hemochromatosis
    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 name
    Porphyria variegata
    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 name
    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 name
    Breast Cancer
    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 name
    Other cancers
    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.


    Pubmed IDLast YearTitleAuthors

    Other Information

    Locus ID:

    NCBI: 3077
    MIM: 613609
    HGNC: 4886
    Ensembl: ENSG00000010704


    dbSNP: 3077
    ClinVar: 3077
    TCGA: ENSG00000010704


    Gene IDTranscript IDUniprot

    Expression (GTEx)


    Protein levels (Protein atlas)

    Not detected


    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA443815Crohn DiseaseDiseaseClinicalAnnotationassociatedPD27115882


    Pubmed IDYearTitleCitations
    208586832010Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.170
    198620102009Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.169
    158581862005Hemochromatosis and iron-overload screening in a racially diverse population.161
    158581862005Hemochromatosis and iron-overload screening in a racially diverse population.161
    181998612008Iron-overload-related disease in HFE hereditary hemochromatosis.137
    181998612008Iron-overload-related disease in HFE hereditary hemochromatosis.137
    118125572002Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA.131
    192545672009Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression.111
    168938962006Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing.105
    199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85


    M Tevfik Dorak

    HFE (hemochromatosis)

    Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

    Online version: http://atlasgeneticsoncology.org/gene/44099/hfe-(hemochromatosis)