Affinage

HFE

Hereditary hemochromatosis protein · UniProt Q30201

Round 2 corrected
Length
348 aa
Mass
40.1 kDa
Annotated
2026-04-28
130 papers in source corpus 25 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HFE is an MHC class I-like cell-surface glycoprotein that serves as a central hepatocyte iron sensor coupling circulating transferrin-iron levels to systemic iron homeostasis through transcriptional regulation of hepcidin. HFE forms a beta2-microglobulin-dependent complex with transferrin receptor 1 (TfR1), competitively reducing TfR1 affinity for diferric transferrin; rising serum iron displaces HFE from TfR1, whereupon free HFE stabilizes the BMP type I receptor ALK3 on the cell surface by inhibiting its ubiquitination, thereby activating HJV-dependent BMP–Smad1/5/8 signalling and hepcidin transcription (PMID:9546397, PMID:18316026, PMID:24904118, PMID:25608116). The C282Y mutation disrupts beta2-microglobulin association and prevents cell-surface expression, while H63D retains surface expression but impairs TfR1 affinity modulation; both cause inappropriately low hepcidin and the iron-loading disorder hereditary hemochromatosis (PMID:8696333, PMID:9356458, PMID:12547226). Hepatocyte TfR1's major nonredundant role in iron homeostasis is interaction with HFE—conditional hepatocyte Tfrc deletion phenocopies constitutive HFE activation, and combined Hfe/Tfrc ablation shows no additive effect (PMID:36322932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Positional cloning identified HFE as the gene mutated in hereditary hemochromatosis, establishing the molecular basis for the most common monogenic iron-overload disorder and revealing that C282Y and H63D are the predominant pathogenic alleles.

    Evidence Linkage-disequilibrium mapping and candidate-gene sequencing in hemochromatosis families

    PMID:8696333

    Open questions at the time
    • Protein function unknown at this stage
    • Mechanism linking mutations to iron overload not established
  2. 1997 High

    Biochemical characterization showed C282Y abolishes beta2-microglobulin binding and traps HFE in the ER, while H63D retains surface expression, explaining genotype-phenotype differences and establishing that surface expression requires beta2-microglobulin association.

    Evidence Co-immunoprecipitation, immunofluorescence, and subcellular fractionation in transfected cells by two independent labs

    PMID:9162021 PMID:9356458

    Open questions at the time
    • Iron-regulatory function of surface HFE unknown
    • Whether H63D alters iron sensing unresolved
  3. 1998 High

    Discovery that HFE forms a complex with TfR1 and reduces its affinity for diferric transferrin, together with the 2.6-Å crystal structure revealing an MHC-like fold with pH-dependent TfR binding, provided the first mechanistic link between HFE and iron uptake regulation.

    Evidence Co-IP, transferrin-binding assays, X-ray crystallography, and surface plasmon resonance at varying pH

    PMID:9465039 PMID:9546397

    Open questions at the time
    • Whether HFE acts solely through reducing TfR1 affinity or has additional signalling functions
    • Physiological tissue context not defined
  4. 1999 High

    Demonstration that HFE competes with transferrin for overlapping sites on TfR1 and that HFE reduces the intracellular labile iron pool via iron-regulatory protein activation unified the structural and functional data into a coherent model of HFE-mediated iron sensing.

    Evidence SPR competition assays, radioactive iron uptake, IRP gel-shift in stable HFE-expressing cells, co-IP from duodenal crypt enterocytes

    PMID:10556042 PMID:10572108 PMID:9990067

    Open questions at the time
    • Systemic signalling mechanism unknown—hepcidin not yet connected
    • Relative importance of duodenal versus hepatocyte HFE unclear
  5. 2000 High

    The 2.8-Å HFE–TfR co-crystal structure revealed the binding interface and showed how HFE grasps the TfR dimer, while cell biology experiments proved that TfR1 binding is required for both endosomal trafficking and iron-regulatory activity of HFE.

    Evidence X-ray crystallography of the HFE–TfR complex; polarized epithelial cell transfection with TfR-binding-impaired and chimeric HFE mutants

    PMID:10638746 PMID:11146662

    Open questions at the time
    • How endosomal localisation couples to downstream regulation unclear
    • In vivo physiological confirmation in mouse models lacking
  6. 2002 High

    Two key advances established that HFE also inhibits macrophage iron efflux independently of TfR1 competition, and that Hfe is required for hepatic hepcidin induction in response to iron loading, connecting HFE to the master iron-regulatory hormone.

    Evidence Iron efflux assays in macrophages from HH patients and THP-1 cells; hepcidin qRT-PCR in Hfe knockout mice with carbonyl-iron loading

    PMID:12429850 PMID:12547226

    Open questions at the time
    • Direct mechanism of HFE-to-hepcidin signal transduction undefined
    • Whether macrophage and hepatocyte functions are connected unknown
  7. 2008 High

    Genetic mouse models with engineered Tfr1 mutations showed that HFE induces hepcidin specifically when displaced from TfR1 by rising diferric transferrin, establishing the iron-sensing switch model in which TfR1 sequesters HFE and iron saturation liberates it to activate hepcidin signalling.

    Evidence Knock-in mouse strains with constitutive or abolished Hfe–Tfr1 interaction; liver-specific Hfe transgene in Hfe-null mice

    PMID:18316026

    Open questions at the time
    • Identity of the downstream signalling pathway activated by free HFE unknown
    • Direct effector interaction not identified
  8. 2010 High

    Hepatocyte-specific Hfe rescue and epistasis with Tfr2 demonstrated that both Hfe and Tfr2 must be present in hepatocytes for normal hepcidin regulation, though whether they form a physical complex in vivo remained disputed.

    Evidence AAV2/8 hepatocyte-specific gene delivery in Hfe-null and Tfr2-deficient mice; co-IP from liver lysates (2012 follow-up found no interaction)

    PMID:20177050 PMID:22460705

    Open questions at the time
    • Nature of HFE–TFR2 cooperation (physical complex vs. parallel pathways) unresolved
    • Downstream effectors still unidentified
  9. 2014 High

    The downstream effector was identified: HFE associates with the BMP type I receptor ALK3, inhibits its ubiquitination, and stabilises it at the cell surface to activate Smad1/5/8 phosphorylation and hepcidin transcription; both C282Y and H63D mutations abolish ALK3 stabilisation.

    Evidence Co-IP of HFE–ALK3, ubiquitination assays, surface biotinylation in Hep3B cells, and reduced ALK3 protein in Hfe knockout mouse liver

    PMID:24904118

    Open questions at the time
    • Structural basis of the HFE–ALK3 interaction unknown
    • Whether HFE directly contacts ALK3 or acts through an adaptor not determined
  10. 2015 High

    Genetic epistasis with HJV placed HFE upstream of the HJV-dependent BMP–Smad pathway: double-knockout Hfe/Hjv mice phenocopied Hjv-null animals, showing HFE's hepcidin-inducing capacity depends on intact HJV–BMP signalling.

    Evidence Hfe/Hjv single- and double-knockout mice with acute iron challenge; Smad1/5/8 phosphorylation immunoblot; hepcidin mRNA quantification

    PMID:25608116

    Open questions at the time
    • Precise molecular ordering of HFE, ALK3, and HJV in the signalling complex not defined
    • Whether HFE regulates BMP ligand availability in addition to receptor stability unknown
  11. 2023 High

    Conditional hepatocyte TfR1 ablation proved that TfR1's major nonredundant hepatocyte function is interaction with HFE to regulate hepcidin, and that this pathway is modulated by serum iron and contributes to hepcidin suppression in β-thalassemia.

    Evidence Hepatocyte-specific Tfrc conditional knockout combined with Hfe KO and β-thalassemia mouse models; comprehensive iron and erythropoietic phenotyping

    PMID:36322932

    Open questions at the time
    • Whether erythroferrone and HFE/TfR1 pathways converge on the same Smad complex not tested
    • Quantitative contribution of HFE pathway versus ERFE pathway in disease states undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the HFE–ALK3 interaction, the precise mechanism by which HFE inhibits ALK3 ubiquitination, and the molecular architecture of the hepatocyte iron-sensing complex (HFE, TFR2, HJV, ALK3) remain undefined.
  • No structure of HFE–ALK3 complex available
  • Ubiquitin ligase targeting ALK3 in HFE absence not identified
  • Whether HFE, TFR2, HJV, and ALK3 form a single signalling complex or operate in parallel remains unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
ACVRL1B2MHJVTFR2TFRC
Complex memberships
HFE–beta2-microglobulin–TfR1 complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 HFE (originally called HLA-H) was identified as a novel MHC class I-like gene mutated in hereditary haemochromatosis; the C282Y missense mutation was found homozygous in ~83% of patients, and a second variant H63D was enriched in compound heterozygous patients. Positional cloning by linkage-disequilibrium and haplotype analysis; sequencing of candidate gene Nature genetics High 8696333
1997 The C282Y mutation abolishes HFE association with beta2-microglobulin and prevents cell-surface expression, causing retention in the ER/middle Golgi and accelerated degradation; the H63D mutation does not affect beta2-microglobulin binding or surface expression. Co-immunoprecipitation, immunofluorescence, subcellular fractionation in transfected COS-7 and human embryonic kidney cells Proceedings of the National Academy of Sciences / Journal of Biological Chemistry High 9162021 9356458
1997 HFE protein is associated with beta2-microglobulin and the transferrin receptor (TfR) in human placenta syncytiotrophoblasts at the apical membrane, placing HFE at the site of maternal-fetal iron transfer. Immunohistochemistry and Western blot co-association from placental membrane fractions Proceedings of the National Academy of Sciences of the United States of America Medium 9371823
1998 HFE forms a stable complex with the transferrin receptor (TfR) and lowers TfR affinity for iron-loaded transferrin; the C282Y mutation prevents HFE–TfR association while the H63D mutation allows binding but impairs the affinity reduction. Co-immunoprecipitation of transfected 293 cells; cell-associated transferrin binding assays; addition of soluble HFE/beta2m to cultured cells Proceedings of the National Academy of Sciences of the United States of America High 9465039
1998 Crystal structure of HFE at 2.6 Å reveals an MHC-like fold with the hemochromatosis mutation sites mapped; HFE binds TfR tightly at neutral pH but not at acidic endosomal pH, consistent with pH-dependent dissociation in endosomes; TfR:HFE stoichiometry is 2:1, distinct from TfR:transferrin 2:2, yet HFE, transferrin, and TfR form a ternary complex. X-ray crystallography (2.6 Å); surface plasmon resonance binding at varying pH; biochemical co-complex analysis Cell High 9546397
1999 HFE protein is physically associated with TfR and beta2-microglobulin in crypt enterocytes of the human duodenum; crypt cells show dramatically higher transferrin-bound iron uptake than villus cells, supporting a role for the HFE–TfR complex in sensing body iron status in crypt enterocytes. Immunocytochemistry; Western blot co-immunoprecipitation from duodenal enterocyte fractions; radiolabeled iron uptake assays in isolated crypt and villus cells Proceedings of the National Academy of Sciences of the United States of America High 9990067
1999 HFE overexpression in stably transfected HeLa cells decreases iron uptake from diferric transferrin and activates iron-regulatory proteins (IRPs), leading to downregulation of ferritin and upregulation of TfR, indicating HFE reduces the intracellular labile iron pool. Stable tetracycline-regulated HFE transfection; radioactive iron uptake assay; IRP gel-shift assay; Western blot Blood High 10572108
1999 HFE competes with transferrin for binding to TfR by binding at or near the transferrin binding site rather than acting allosterically; the Fe-Tf:TfR:HFE ternary complex contains one Fe-Tf and one HFE bound to the TfR homodimer. Radioactivity-based and surface plasmon resonance (biosensor) competition assays with soluble proteins Journal of molecular biology High 10556042
2000 Crystal structure of the HFE–TfR extracellular complex at 2.8 Å: two HFE molecules grasp each side of the TfR dimer, with HFE helices (the counterpart of the MHC peptide-binding groove) making extensive contacts with TfR helices in the dimerization domain; TfR alone and in complex differ in domain arrangement, suggesting a communication mechanism between TfR chains. X-ray crystallography at 2.8 Å of the co-complex of soluble HFE and TfR ectodomains Nature High 10638746
2000 Binding of HFE to TfR is required for trafficking of HFE to endosomes and for regulation of intracellular iron homeostasis (ferritin reduction, TfR upregulation); a TfR-binding-impaired HFE mutant accumulates at the basolateral surface but fails to regulate iron; restoring endosomal targeting by an LDLR endosomal-targeting sequence does not rescue iron regulation, indicating TfR binding per se is required. Stable transfection of polarized duodenal epithelial cells; immunofluorescence localization; ferritin and TfR Western blots; chimeric protein rescue experiments Nature cell biology High 11146662
2000 In HFE-transfected human hepatoma cells, HFE–GFP forms a complex with endogenous TfR and beta2-microglobulin, decreases TfR affinity for transferrin (Kd shift from 1.9 to 4.3 nM), reduces the rate of TfR-dependent iron uptake, and slows transferrin recycling from endosome to cell surface. Co-immunoprecipitation; 59Fe and 125I-transferrin uptake/release assays; Scatchard analysis; pulse-chase recycling assay in HLF hepatoma cells Biochimica et biophysica acta Medium 10771090
2001 Mutational analysis of TfR reveals that five residues at the HFE binding site (L619, R629, Y643, G647, F650) are also required for transferrin binding, confirming that HFE and transferrin compete for overlapping sites on TfR; solution studies show a 2:2 TfR:HFE complex can form at sub-micromolar concentrations. Site-directed mutagenesis of TfR; surface plasmon resonance binding assays; equilibrium gel-filtration; analytical ultracentrifugation Journal of molecular biology High 11800564
2002 Wild-type HFE raises cellular iron by inhibiting iron efflux from macrophages (THP-1 cell line and primary macrophages), independent of its competition with transferrin for TfR binding; the H41D HFE mutant loses the ability to inhibit iron release despite retaining TfR binding. Iron efflux assays in THP-1 monocyte/macrophage cells and primary macrophages from healthy donors and HH patients; HFE transfection; competitive inhibition with transferrin Proceedings of the National Academy of Sciences of the United States of America High 12429850
2002 Hfe knockout mice show significantly decreased liver hepcidin mRNA at 4 weeks compared to wild-type, and fail to upregulate hepcidin in response to carbonyl-iron loading (5-fold induction in wild-type vs. none in Hfe-/-), establishing that Hfe is required for appropriate hepcidin induction in response to iron stores. Quantitative RT-PCR of hepcidin mRNA in liver; dietary iron loading experiments; comparison of wild-type vs. Hfe knockout mice at multiple ages Blood cells, molecules & diseases High 12547226
2004 Expression of HFE in HT29 colonic cells increases ferritin levels by inhibiting iron efflux rather than affecting transferrin-mediated iron uptake; this effect is independent of TfR1 interaction (shown with W81A mutant) and is associated with decreased hephaestin mRNA. Stable HFE transfection; ferritin Western blot; 59Fe efflux and uptake assays; real-time RT-PCR The Journal of biological chemistry Medium 15044462
2006 HFE and transferrin receptor 2 (TFR2) interact in cells; this interaction is not abolished by hemochromatosis-associated mutations in either protein; TFR2 competes with TFR1 for HFE binding, suggesting a model in which HFE can signal iron status via either receptor. Co-immunoprecipitation in transfected cells; competition binding assays The Journal of biological chemistry Medium 16893896
2008 Mouse strains engineered to constitutively favour the Hfe/Tfr1 interaction develop iron overload with inappropriately low hepcidin; strains carrying mutations that prevent the Hfe/Tfr1 interaction develop iron deficiency with inappropriately high hepcidin; liver-specific Hfe overexpression in Hfe-/- mice increases hepcidin and causes iron deficiency — establishing that Hfe induces hepcidin expression when displaced from Tfr1. Knock-in mouse strains with engineered Tfr1 mutations; liver-specific Hfe transgene; measurement of serum iron, hepcidin mRNA, and iron parameters Cell metabolism High 18316026
2010 Hepatocyte-specific delivery of Hfe (via AAV) in Hfe-null mice restores hepcidin mRNA and corrects iron overload; Hfe delivery in Tfr2-deficient mice has no effect, and vice versa, demonstrating that both Hfe and Tfr2 must be present in hepatocytes for normal hepcidin regulation and suggesting Hfe is limiting in the Hfe/Tfr2 hepcidin-regulatory complex. AAV2/8 hepatocyte-specific gene delivery; hepcidin RT-PCR; serum and liver iron measurements in Hfe-null and Tfr2-deficient mice Blood High 20177050
2012 Hepatocellular overexpression of Hfe in Tfr2-deficient mice still induces hepcidin and causes iron deficiency/microcytic anemia; co-immunoprecipitation of liver lysates found no evidence for Hfe–Tfr2 physical interaction in vivo, suggesting Hfe-dependent hepcidin induction does not require Tfr2. Hfe transgene expression in Tfr2(Y245X/Y245X) mice; hematological and iron measurements; co-immunoprecipitation from liver lysates American journal of hematology Medium 22460705
2014 HFE overexpression increases Smad1/5/8 phosphorylation and hepcidin expression via the BMP pathway; HFE associates with the BMP type I receptor ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation and increasing ALK3 accumulation at the cell surface; C282Y and H63D HFE mutants both fail to increase ALK3 surface expression; Hfe deletion in mice reduces hepatic ALK3 protein. Hep3B cell overexpression; Smad phosphorylation immunoblot; co-immunoprecipitation of HFE–ALK3; ubiquitination assay; surface biotinylation; Hfe knockout mouse ALK3 expression Blood High 24904118
2014 Wild-type HFE (but not C282Y mutant HFE) inhibits CD8+ T-lymphocyte activation as measured by MIP-1β secretion and 4-1BB expression, independent of MHC I surface levels, beta2-m competition, or TfR interaction; the alpha1-2 domains of HFE mediate this inhibition. Transient HFE transfection in antigen-presenting cells; co-culture with antigen-specific CD8+ T cells; cytokine ELISA; flow cytometry for 4-1BB; domain deletion mutants European journal of immunology Medium 24643698
2015 HJV and HFE regulate hepcidin through distinct mechanisms: Hfe-/-Hjv-/- double-knockout mice phenocopy Hjv-/- for iron overload severity and absence of iron-induced Smad1/5/8 phosphorylation, indicating HFE's ability to induce hepcidin in response to transferrin-bound iron is dependent on HJV-mediated BMP–Smad signalling. Generation of Hfe-/-, Hjv-/-, and Hfe-/-Hjv-/- double-knockout mice; acute iron challenge; hepcidin mRNA quantification; Smad1/5/8 phosphorylation immunoblot Antioxidants & redox signaling High 25608116
2023 Hepatocyte-specific Tfrc (TfR1) knockout mice display inappropriately high hepcidin relative to iron and erythropoietic signals, but ablation of hepatocyte Tfrc has no additional iron phenotype in Hfe knockout mice, demonstrating that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is interaction with HFE to regulate hepcidin; this pathway is modulated by serum iron and contributes to hepcidin suppression in β-thalassemia. Conditional hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre); combined Hfe KO and β-thalassemia mouse models; serum/liver iron, hepcidin, EPO, erythroferrone measurements Blood High 36322932
2001 An endogenous antisense RNA transcribed from the HFE locus (spanning exon 1, exon 2, and part of intron 1 plus ~1 kb upstream) is polyadenylated with no open reading frame and is ubiquitously expressed; in vitro coupled transcription-translation experiments show this antisense RNA decreases HFE protein expression. RACE, RT-PCR, dbEST screening, RNase A protection assay, in vitro transcription-translation Human molecular genetics Low 11532995

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature genetics 3126 8696333
2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2873 20686565
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2011 Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 1610 21909115
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1998 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proceedings of the National Academy of Sciences of the United States of America 662 9465039
1997 Global prevalence of putative haemochromatosis mutations. Journal of medical genetics 660 9138148
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet (London, England) 653 11812557
2005 Hemochromatosis and iron-overload screening in a racially diverse population. The New England journal of medicine 587 15858186
2008 Iron-overload-related disease in HFE hereditary hemochromatosis. The New England journal of medicine 539 18199861
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1998 Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 510 9546397
2010 Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proceedings of the National Academy of Sciences of the United States of America 447 20133674
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1997 The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. The Journal of biological chemistry 433 9162021
2009 A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nature genetics 423 19820697
2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nature genetics 406 20139978
1996 Haemochromatosis and HLA-H. Nature genetics 363 8896550
2010 Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways. Diabetes 361 20858683
2011 Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nature genetics 348 21909110
2010 EASL clinical practice guidelines for HFE hemochromatosis. Journal of hepatology 346 20471131
2004 Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology (Baltimore, Md.) 342 14752836
2001 HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. American journal of epidemiology 331 11479183
1997 Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. American journal of human genetics 330 9106528
1999 HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 329 10194428
1997 Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proceedings of the National Academy of Sciences of the United States of America 312 9356458
2009 Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nature genetics 294 19862010
1997 Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proceedings of the National Academy of Sciences of the United States of America 288 9371823
2000 Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 283 10638746
2008 The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell metabolism 278 18316026
1997 Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet (London, England) 272 9024376
2012 Seventy-five genetic loci influencing the human red blood cell. Nature 266 23222517
2006 Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. The Journal of biological chemistry 257 16893896
2002 Decreased liver hepcidin expression in the Hfe knockout mouse. Blood cells, molecules & diseases 218 12547226
1998 Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology (Baltimore, Md.) 196 9620340
1999 Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proceedings of the National Academy of Sciences of the United States of America 195 9990067
2001 Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 184 11325323
1999 The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. Journal of molecular biology 154 10556042
1999 Multicentric origin of hemochromatosis gene (HFE) mutations. American journal of human genetics 126 10090890
2015 HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene 110 26456104
2002 The hemochromatosis protein HFE inhibits iron export from macrophages. Proceedings of the National Academy of Sciences of the United States of America 105 12429850
2001 Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. Journal of molecular biology 104 11800564
2004 The origin and spread of the HFE-C282Y haemochromatosis mutation. Human genetics 101 15290237
2004 Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences. Journal of the neurological sciences 97 15546588
1998 Hemochromatosis in Ireland and HFE. Blood cells, molecules & diseases 94 9851896
2014 HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood 86 24904118
2009 HFE-associated hereditary hemochromatosis. Genetics in medicine : official journal of the American College of Medical Genetics 79 19444013
1999 HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 78 10572108
1997 Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis. Journal of hepatology 78 9382962
2002 Regulation of iron absorption in Hfe mutant mice. Blood 73 12149232
2010 Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 71 20177050
2003 Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism. Neuroscience letters 71 12902032
2002 H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers. Haematologica 69 11869934
2007 Non-HFE haemochromatosis. World journal of gastroenterology 68 17729390
2003 Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proceedings of the National Academy of Sciences of the United States of America 68 14673107
2000 Contribution of different HFE genotypes to iron overload disease: a pooled analysis. Genetics in medicine : official journal of the American College of Medical Genetics 66 11399207
1999 Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Human molecular genetics 61 10401000
2000 Histological evaluation of iron in liver biopsies: relationship to HFE mutations. The American journal of gastroenterology 60 10925986
2015 The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genetics in medicine : official journal of the American College of Medical Genetics 59 26633544
2006 The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free radical biology & medicine 58 16678024
2005 Non-HFE hemochromatosis. Seminars in liver disease 57 16315138
2001 Molecular aspects of iron absorption and HFE expression. Gastroenterology 56 11729128
2017 Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Haematologica 54 28280078
2006 Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation. American journal of physiology. Gastrointestinal and liver physiology 54 16565419
2000 Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity. Blood cells, molecules & diseases 52 11001626
2001 HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls. European journal of human genetics : EJHG 50 11840200
1997 Clinical and family studies in genetic hemochromatosis: microsatellite and HFE studies in five atypical families. Hepatology (Baltimore, Md.) 49 9328324
2006 Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. AIDS (London, England) 44 16847405
2001 Hereditary hemochromatosis since discovery of the HFE gene. Clinical chemistry 43 11427444
2012 Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2. American journal of hematology 42 22460705
2004 Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells. The Journal of biological chemistry 41 15044462
2002 Frequency of the S65C mutation of HFE and iron overload in 309 subjects heterozygous for C282Y. Journal of hepatology 41 11943417
2000 Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis. Nature cell biology 41 11146662
1999 The hereditary hemochromatosis gene (HFE): a MHC class I-like gene that functions in the regulation of iron homeostasis. Immunologic research 41 10580641
2020 The roles of iron and HFE genotype in neurological diseases. Molecular aspects of medicine 40 32654761
2000 Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells. Biochimica et biophysica acta 39 10771090
2006 Iron Imports. VI. HFE and regulation of intestinal iron absorption. American journal of physiology. Gastrointestinal and liver physiology 38 16537971
2019 Hemochromatosis: Hereditary hemochromatosis and HFE gene. Vitamins and hormones 35 30798813
2011 Iron metabolism and the role of HFE gene polymorphisms in Wilson disease. Liver international : official journal of the International Association for the Study of the Liver 35 22098612
2003 Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda. Archives of dermatology 35 12622622
2010 Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Human genetics 34 20607553
2008 Function of the hemochromatosis protein HFE: Lessons from animal models. World journal of gastroenterology 34 19058322
2014 Molecular basis of HFE-hemochromatosis. Frontiers in pharmacology 33 24653703
1999 Polymorphisms in the HFE gene. Human heredity 33 9858853
2023 Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia. Blood 32 36322932
2012 Non-HFE hemochromatosis. Revista brasileira de hematologia e hemoterapia 32 23049448
2019 Diagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect. Gastroenterology research 29 31636772
2005 Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway. Digestion 29 16103673
2011 HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women. Molecular and cellular biochemistry 28 21625954
2009 Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1. Journal of neuroinflammation 28 19228389
2002 A previously undescribed nonsense mutation of the HFE gene. Clinical genetics 28 11903354
2000 Differential HFE allele expression in hemochromatosis heterozygotes. Gastroenterology 28 11040194
1999 Mutation analysis of the HFE gene in Brazilian populations. Blood cells, molecules & diseases 28 10660479
2013 Non-HFE hemochromatosis: pathophysiological and diagnostic aspects. Clinics and research in hepatology and gastroenterology 26 24321703
2012 Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. Blood cells, molecules & diseases 26 22244935
2002 Frequency of the HFE gene mutations in five Italian populations. Blood cells, molecules & diseases 26 12547216
2010 Hepcidin and Hfe in iron overload in beta-thalassemia. Annals of the New York Academy of Sciences 25 20712796
2002 Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders. Haematologica 25 11836162
1997 Impact of HLA-H mutations on iron stores in healthy elderly men and women. Blood cells, molecules & diseases 25 9410471
2003 Association between the HFE mutations and longevity: a study in Sardinian population. Mechanisms of ageing and development 24 12714263
2002 Mutations in the hemochromatosis gene (HFE) and stroke. Stroke 24 12364722
2013 Telomere length and elevated iron: the influence of phenotype and HFE genotype. American journal of hematology 23 23512844
2008 Clinical penetrance of C282Y homozygous HFE hemochromatosis. Expert review of hematology 23 21082925
2007 The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis. Annals of the rheumatic diseases 22 17284543
2007 HFE gene in primary and secondary hepatic iron overload. World journal of gastroenterology 22 17729389
1999 Mutations of the HFE gene and the risk of hepatocellular carcinoma. Blood cells, molecules & diseases 22 10660482
2005 Frequency of hemochromatosis gene (HFE) mutations in Russian healthy women and patients with estrogen-dependent cancers. Biochimica et biophysica acta 21 16216474
2001 Identification of an endogenous RNA transcribed from the antisense strand of the HFE gene. Human molecular genetics 21 11532995
2019 HLAIb worldwide genetic diversity: New HLA-H alleles and haplotype structure description. Molecular immunology 20 31078115
2008 The role of Hfe in transferrin-bound iron uptake by hepatocytes. Hepatology (Baltimore, Md.) 20 18393371
2017 A role for sex and a common HFE gene variant in brain iron uptake. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 19 28350201
2015 HJV and HFE Play Distinct Roles in Regulating Hepcidin. Antioxidants & redox signaling 19 25608116
2014 The WT hemochromatosis protein HFE inhibits CD8⁺ T-lymphocyte activation. European journal of immunology 19 24643698
2005 Mutations in the hemochromatosis gene (HFE) and multiple sclerosis. Neuroscience letters 19 15955425
2002 HFE gene mutations and iron metabolism in Wilson's disease. Liver 19 12445172
2000 The C282Y mutation of the HFE gene is not found in Chinese haemochromatotic patients: multicentre retrospective study. Hong Kong medical journal = Xianggang yi xue za zhi 19 10895137
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2009 Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk. Pediatric blood & cancer 18 19711434
2002 Hemochromatosis (HFE) and transferrin receptor-1 (TFRC1) genes in sporadic porphyria cutanea tarda (sPCT). Cellular and molecular biology (Noisy-le-Grand, France) 18 11929045
2000 Prevalence and clinical significance of HFE gene mutations in patients with iron overload. The American journal of gastroenterology 18 11051367
2002 HFE and non-HFE hemochromatosis. International journal of hematology 17 12416729
1999 Update on hereditary hemochromatosis and the HFE gene. Mayo Clinic proceedings 17 10488796
2014 Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE). Hematology/oncology clinics of North America 16 25064704
2009 HFE gene mutations and iron status of Brazilian blood donors. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 16 20027482
2008 Does the SLC40A1 gene modify HFE-related haemochromatosis phenotypes? Annals of hematology 16 18820912
2004 Iron, the HFE gene, and hepatitis C. Clinics in liver disease 16 15464655
2000 Relation between HFE mutations and mild iron-overload expression. Molecular genetics and metabolism 16 10870847
2000 The structure and function of HFE. BioEssays : news and reviews in molecular, cellular and developmental biology 16 10878571