HFE (hemochromatosis)

Identity

Other names	HFE1
	HH
	HLA-H
	MGC103790
	dJ221C16.10.1
Hugo	HFE
Location	6p22.1

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
Hugo	HFE
GDB	HFE
Entrez_Gene	HFE  3077  hemochromatosis
	Cards
Atlas	HFEID44099ch6p22
GeneCards	HFE
Ensembl	HFE [Search_View]   ENSG00000010704 [Gene_View]
Genatlas	HFE
GeneLynx	HFE
eGenome	HFE
euGene	3077
	Genomic and cartography
GoldenPath	HFE  -  6p22.1   chr6:26195488-26203448 +  6p21.3   [Description]    (hg18-Mar_2006)
Ensembl	HFE - 6p21.3 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	HFE
	Gene and transcription
Genbank	AF079407 [ ENTREZ ]
Genbank	AF079408 [ ENTREZ ]
Genbank	AF079409 [ ENTREZ ]
Genbank	AF109385 [ ENTREZ ]
Genbank	AF115264 [ ENTREZ ]
RefSeq	NM_000410 [ SRS ]    NM_000410 [ ENTREZ ]
RefSeq	NM_139002 [ SRS ]    NM_139002 [ ENTREZ ]
RefSeq	NM_139003 [ SRS ]    NM_139003 [ ENTREZ ]
RefSeq	NM_139004 [ SRS ]    NM_139004 [ ENTREZ ]
RefSeq	NM_139005 [ SRS ]    NM_139005 [ ENTREZ ]
RefSeq	NM_139006 [ SRS ]    NM_139006 [ ENTREZ ]
RefSeq	NM_139007 [ SRS ]    NM_139007 [ ENTREZ ]
RefSeq	NM_139008 [ SRS ]    NM_139008 [ ENTREZ ]
RefSeq	NM_139009 [ SRS ]    NM_139009 [ ENTREZ ]
RefSeq	NM_139010 [ SRS ]    NM_139010 [ ENTREZ ]
RefSeq	NM_139011 [ SRS ]    NM_139011 [ ENTREZ ]
RefSeq	AC_000049 [ SRS ]    AC_000049 [ ENTREZ ]
RefSeq	NC_000006 [ SRS ]    NC_000006 [ ENTREZ ]
RefSeq	NG_001335 [ SRS ]    NG_001335 [ ENTREZ ]
RefSeq	NT_007592 [ SRS ]    NT_007592 [ ENTREZ ]
RefSeq	NW_922984 [ SRS ]    NW_922984 [ ENTREZ ]
AceView	HFE AceView - NCBI
Unigene	Hs.233325 [ SRS ]    Hs.233325 [ NCBI ]     HS233325 [ spliceNest ]
Fast-db	4231 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q30201 [ SRS]    Q30201 [ EXPASY ]     Q30201 [ INTERPRO ]
Prosite	PS50835 IG_LIKE [ SRS ]    PS50835 IG_LIKE [ Expasy ]
Prosite	PS00290 IG_MHC [ SRS ]    PS00290 IG_MHC [ Expasy ]
Interpro	IPR007110 Ig-like [ SRS ]    IPR007110 Ig-like [ EBI ]
Interpro	IPR013783 Ig-like_fold [ SRS ]    IPR013783 Ig-like_fold [ EBI ]
Interpro	IPR003006 Ig/MHC_CS [ SRS ]    IPR003006 Ig/MHC_CS [ EBI ]
Interpro	IPR003597 Ig_C1-set [ SRS ]    IPR003597 Ig_C1-set [ EBI ]
Interpro	IPR011161 MHC_I-like_Ag-recog [ SRS ]    IPR011161 MHC_I-like_Ag-recog [ EBI ]
Interpro	IPR001039 MHC_I_a_a1/a2 [ SRS ]    IPR001039 MHC_I_a_a1/a2 [ EBI ]
CluSTr	Q30201
Pfam	PF07654 C1-set [ SRS ]    PF07654 C1-set [ Sanger ]    pfam07654 [ NCBI-CDD ]
Pfam	PF00129 MHC_I [ SRS ]    PF00129 MHC_I [ Sanger ]    pfam00129 [ NCBI-CDD ]
Smart	SM00407 IGc1 [EMBL]
Blocks	Q30201
PDB	1A6Z [ SRS ]    1A6Z [ PdbSum ],   1A6Z [ IMB ]   1A6Z [ RSDB ]
PDB	1C42 [ SRS ]    1C42 [ PdbSum ],   1C42 [ IMB ]   1C42 [ RSDB ]
PDB	1DE4 [ SRS ]    1DE4 [ PdbSum ],   1DE4 [ IMB ]   1DE4 [ RSDB ]
HPRD	01993
	Protein Interaction databases
DIP	Q30201
IntAct	Q30201
	Polymorphism : SNP, mutations, diseases
OMIM	176200;235200    [ map ]
GENECLINICS	176200;235200
SNP	HFE [dbSNP-NCBI]
SNP	NM_000410 [SNP-NCI]
SNP	NM_139002 [SNP-NCI]
SNP	NM_139003 [SNP-NCI]
SNP	NM_139004 [SNP-NCI]
SNP	NM_139005 [SNP-NCI]
SNP	NM_139006 [SNP-NCI]
SNP	NM_139007 [SNP-NCI]
SNP	NM_139008 [SNP-NCI]
SNP	NM_139009 [SNP-NCI]
SNP	NM_139010 [SNP-NCI]
SNP	NM_139011 [SNP-NCI]
SNP	HFE [GeneSNPs - Utah]  HFE] [HGBASE - SRS]
HAPMAP	HFE [HAPMAP]
HGMD	HFE
	General knowledge
Family Browser	HFE [UCSC Family Browser]
SOURCE	NM_000410
SOURCE	NM_139002
SOURCE	NM_139003
SOURCE	NM_139004
SOURCE	NM_139005
SOURCE	NM_139006
SOURCE	NM_139007
SOURCE	NM_139008
SOURCE	NM_139009
SOURCE	NM_139010
SOURCE	NM_139011
SMD	Hs.233325
SAGE	Hs.233325
GO	antigen processing and presentation of peptide antigen via MHC class I [Amigo]  antigen processing and presentation of peptide antigen via MHC class I
GO	iron ion binding [Amigo]  iron ion binding
GO	cytoplasm [Amigo]  cytoplasm
GO	plasma membrane [Amigo]  plasma membrane
GO	integral to plasma membrane [Amigo]  integral to plasma membrane
GO	protein complex assembly [Amigo]  protein complex assembly
GO	ion transport [Amigo]  ion transport
GO	iron ion transport [Amigo]  iron ion transport
GO	cellular iron ion homeostasis [Amigo]  cellular iron ion homeostasis
GO	receptor-mediated endocytosis [Amigo]  receptor-mediated endocytosis
GO	immune response [Amigo]  immune response
GO	membrane [Amigo]  membrane
GO	antigen processing and presentation [Amigo]  antigen processing and presentation
GO	MHC class I protein complex [Amigo]  MHC class I protein complex
PubGene	HFE
TreeFam	HFE
CTD	3077 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	HFE Related clones (RZPD - Berlin)
	PubMed
PubMed	213 Pubmed reference(s) in LocusLink

Bibliography

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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.

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PMID 9788468

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PMID 9482913

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The C282Y mutation of HFE is another male-specific risk factor for childhood acute lymphoblastic leukemia.

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Blood. 1999 ; 94 (11) : page 3957.

PMID 10627122

Prevalence of hemochromatosis related HFE gene mutations in patients with acute myeloid leukemia.

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Leukemia research. 1999 ; 23 (6) : 597-598.

PMID 10374855

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PMID 11096344

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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.

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PMID 11114371

Iron transport in a lymphoid cell line with the hemochromatosis C282Y mutation.

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PMID 11313265

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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.

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PMID 11591868

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PMID 11836162

Sequence variation and haplotype structure at the human HFE locus.

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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.

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PMID 12606179

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PMID 14643418

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PMID 12529348

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PMID 12706501

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PMID 12948285

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PMID 12969816

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PMID 15018631

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PMID 14670915

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PMID 14973098

Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer.

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PMID 15894659

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PMID 15775751

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PMID 15863206

HFE H63D variant and leukemia susceptibility.

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PMID 17107894

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PMID 16503999

The significance of the hemochromatosis genetic variants in multiple myeloma in comparison to that of myelodysplastic syndrome.

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PMID 17001480

HFE gene mutations in patients with acute leukemia.

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PMID 17107905

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Contributor(s)

Written	03-2008	M 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:23:57 2008