HFE (hemochromatosis)

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HFE (hemochromatosis)

Written	2008-03	M Tevfik Dorak
		Genomic Immunoepidemiology Laboratory, HUMIGEN LLC, The Institute for Genetic Immunology, Hamilton, NJ 08690-3303, USA

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)	HFE1
	HH
	HLA-H
	MGC103790
	dJ221C16.10.1
HGNC (Hugo)	HFE
HGNC Alias symb	HLA-H
	HFE1
HGNC Alias name	high Fe
HGNC Previous name	hemochromatosis
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)

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 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.

Note

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.

	Nomenclature
HGNC (Hugo)	HFE 4886
LRG (Locus Reference Genomic)	LRG_748
	Cards
Atlas	HFEID44099ch6p22
Entrez_Gene (NCBI)	HFE homeostatic iron regulator
Aliases	HFE1; HH; HLA-H; MVCD7;
	TFQTL2
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 DataPortal	ENSG00000010704
TCGA cBioPortal	HFE
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)
GoldenPath	HFE - 6p22.2 [CytoView hg19] HFE - 6p22.2 [CytoView hg38]
ImmunoBase	ENSG00000010704
Genome Data Viewer NCBI	HFE [Mapview hg19]
OMIM	104300 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 Expression	HFE [ NCBI-GEO ] HFE [ EBI - ARRAY_EXPRESS ] HFE [ SEEK ] HFE [ MEM ]
Gene Expression Viewer (FireBrowse)	HFE [ Firebrowse - Broad ]
Genevisible	Expression of HFE in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	3077
GTEX Portal (Tissue expression)	HFE
Human Protein Atlas	ENSG00000010704-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]
HPRD	01993
	Protein Interaction databases
BioGRID	HFE
STRING (EMBL)	HFE
ZODIAC	HFE
	Ontologies - Pathways
	Litterature
PubMed	499 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
EVEX	HFE

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed