hfe (gene) hfe (gene) human homeostatic iron regulator protein, also known as the hfe protein (high fe2+), is a transmembrane protein which in humans is encoded by the hfe gene. the hfe gene is located on short arm of chromosome 6 at location 6p22.2 not to be confused with hemochromatosis. hfeavailable structurespdbortholog search: pdbe rcsb list of pdb id codes1de4, 1a6zidentifiersaliaseshfe, hfe1, hh, hla-h, mvcd7, tfqtl2, hfe gene, hemochromatosis, homeostatic iron regulatorexternal idsomim: 613609 mgi: 109191 homologene: 88330 genecards: hfe gene location (human)chr.chromosome 6 (human)band6p22.2start26,087,281 bpend26,098,343 bpgene location (mouse)chr.chromosome 13 (mouse)band13 a3.1|13 9.88 cmstart23,886,017 bpend23,894,837 bprna expression patternbgeehumanmouse (ortholog)top expressed instromal cell of endometriummonocytesmooth muscle tissuecervix epitheliumseminal vesiculaleft adrenal glandachilles tendongallbladderliverpancreatic ductal celltop expressed inleft lobe of liverwhite adipose tissueright ventriclecarotid bodymyocardium of ventricletriceps brachii musclesubcutaneous adipose tissueolfactory epitheliumanklevastus lateralis musclemore reference expression databiogpsmore reference expression datagene ontologymolecular function peptide antigen binding beta-2-microglobulin binding co-receptor binding protein binding transferrin receptor binding signaling receptor binding natural killer cell lectin-like receptor binding cellular component integral component of membrane recycling endosome hfe-transferrin receptor complex membrane basal part of cell plasma membrane apical part of cell integral component of plasma membrane terminal web early endosome mhc class i protein complex perinuclear region of cytoplasm cytoplasmic vesicle external side of plasma membrane extracellular space biological process negative regulation of t cell antigen processing and presentation positive regulation of peptide hormone secretion positive regulation of receptor-mediated endocytosis cellular response to iron ion antigen processing and presentation negative regulation of receptor binding regulation of protein localization to cell surface antigen processing and presentation of peptide antigen via mhc class i female pregnancy positive regulation of pathway-restricted smad protein phosphorylation response to iron ion starvation iron ion homeostasis negative regulation of antigen processing and presentation of endogenous peptide antigen via mhc class i ion transport bmp signaling pathway cellular response to iron ion starvation response to iron ion multicellular organismal iron ion homeostasis positive regulation of ferrous iron binding positive regulation of transferrin receptor binding positive regulation of signaling receptor activity liver regeneration positive regulation of gene expression negative regulation of t cell cytokine production acute-phase response negative regulation of proteasomal ubiquitin-dependent protein catabolic process negative regulation of ubiquitin-dependent protein catabolic process positive regulation of receptor binding negative regulation of signaling receptor activity positive regulation of protein binding hormone biosynthetic process negative regulation of cd8-positive, alpha-beta t cell activation cellular iron ion homeostasis iron ion import across plasma membrane transferrin transport protein-containing complex assembly t cell mediated cytotoxicity immune response natural killer cell activation natural killer cell mediated cytotoxicity susceptibility to natural killer cell mediated cytotoxicity regulation of iron ion transport sources:amigo / quickgoorthologsspecieshumanmouseentrez307715216ensemblensg00000010704ensmusg00000006611uniprotq30201p70387refseq (mrna)nm_000410nm_001300749nm_139002nm_139003nm_139004nm_139005nm_139006nm_139007nm_139008nm_139009nm_139010nm_139011nm_001384164nm_010424nm_001347493refseq (protein)np_000401np_001287678np_620572np_620573np_620575np_620576np_620577np_620578np_620579np_620580np_001371093np_001334422np_034554location (ucsc)chr 6: 26.09 – 26.1 mbchr 13: 23.89 – 23.89 mbpubmed searchwikidataview/edit humanview/edit mouse function the protein encoded by this gene is an integral membrane protein that is similar to mhc class i-type proteins and associates with beta-2 microglobulin (beta2m). it is thought that this protein functions to regulate circulating iron uptake by regulating the interaction of the transferrin receptor with transferrin. the hfe gene contains 7 exons spanning 12 kb. the full-length transcript represents 6 exons. hfe protein is composed of 343 amino acids. there are several components, in sequence: a signal peptide (initial part of the protein), an extracellular transferrin receptor-binding region (α1 and α2), a portion that resembles immunoglobulin molecules (α3), a transmembrane region that anchors the protein in the cell membrane, and a short cytoplasmic tail. hfe expression is subjected to alternative splicing. the predominant hfe full-length transcript has ~4.2 kb. alternative hfe splicing variants may serve as iron regulatory mechanisms in specific cells or tissues. hfe is prominent in small intestinal absorptive cells, gastric epithelial cells, tissue macrophages, and blood monocytes and granulocytes, and the syncytiotrophoblast, an iron transport tissue in the placenta. clinical significance the iron storage disorder hereditary hemochromatosis (hhc) is an autosomal recessive genetic disorder that usually results from defects in this gene. the disease-causing genetic variant most commonly associated with hemochromatosis is p. c282y. about 1/200 of people of northern european origin have two copies of this variant; they, particularly males, are at high risk of developing hemochromatosis. this variant may also be one of the factors modifying wilson's disease phenotype, making the symptoms of the disease appear earlier. allele frequencies of hfe c282y in ethnically diverse western european white populations are 5-14% and in north american non-hispanic whites are 6-7%. c282y exists as a polymorphism only in western european white and derivative populations, although c282y may have arisen independently in non-whites outside europe. hfe h63d is cosmopolitan but occurs with greatest frequency in individuals of european descent. allele frequencies of h63d in ethnically diverse western european populations are 10-29%. and in north american non-hispanic whites are 14-15%. at least 42 mutations involving hfe introns and exons have been discovered, most of them in persons with hemochromatosis or their family members. most of these mutations are rare. many of the mutations cause or probably cause hemochromatosis phenotypes, often in compound heterozygosity with hfe c282y. other mutations are either synonymous or their effect on iron phenotypes, if any, has not been demonstrated.