HFE Gene - Hereditary Hemochromatosis Protein
Key regulator of iron homeostasis and primary gene associated with hereditary hemochromatosis
Gene Information Card
| Symbol | HFE |
|---|---|
| Full Name | Homeostatic Iron Regulator |
| Gene Type | Protein coding |
| Chromosomal Location | 6p22.2 |
| NCBI Gene ID | 3077 ncbi.nlm.nih.gov/gene/3077 |
| Ensembl ID | ENSG00000010704 |
| UniProt ID | Q30201 |
| OMIM ID | 613609 |
| HGNC ID | 4886 |
| Aliases | HFE1, HH, HLA-H, MVCD7, TFQTL2 |
Description
The HFE gene encodes a membrane protein that is structurally similar to major histocompatibility complex (MHC) class I molecules. It forms a complex with beta-2 microglobulin and interacts with the transferrin receptor (TFRC) to regulate iron uptake. Mutations in HFE disrupt iron sensing and lead to excessive intestinal iron absorption, causing hereditary hemochromatosis. The gene is primarily expressed in the liver, duodenum, and immune cells.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hereditary Hemochromatosis (HH) | Loss-of-function mutations (e.g., C282Y) impair HFE binding to TFRC, reducing hepcidin expression and causing iron overload. | ClinVar, OMIM |
| Porphyria Cutanea Tarda (PCT) | HFE mutations exacerbate iron accumulation, triggering uroporphyrinogen decarboxylase inhibition. | ClinVar, NCBI |
| Type 2 Diabetes (associated) | Iron overload from HFE mutations damages pancreatic beta cells, impairing insulin secretion. | OMIM, NCBI |
| Hepatocellular Carcinoma | Chronic iron overload leads to oxidative stress, fibrosis, and increased cancer risk. | COSMIC, NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Duodenum | 8.3 | Medium |
| Spleen | 6.1 | Low |
| Bone Marrow | 4.7 | Low |
| Heart | 3.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | 15.2 | Hepatocyte model |
| Caco-2 (intestinal) | 9.8 | Enterocyte model |
| THP-1 (monocyte) | 7.4 | Macrophage-like |
| K562 (erythroleukemia) | 5.1 | Erythroid precursor |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.845G>A (p.Cys282Tyr, C282Y) | Missense | ~5-10% in Caucasians | Disrupts HFE-TFRC interaction, reduces hepcidin, causes iron overload. |
| c.187C>G (p.His63Asp, H63D) | Missense | ~15-20% in Caucasians | Mild effect; compound heterozygosity with C282Y increases HH risk. |
| c.193A>T (p.Ser65Cys, S65C) | Missense | ~1-2% | Rare; mild iron overload association. |
| c.277G>C (p.Glu93Gln, E93Q) | Missense | <1% | Uncertain significance; reported in HH cases. |
Mutation functional classification
Loss of Function (LOF)
C282Y and H63D are loss-of-function mutations that impair HFE protein folding, cell surface expression, and interaction with TFRC, leading to reduced hepcidin transcription and unregulated iron absorption.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported for HFE.
Dominant Negative (DN)
C282Y may exert a dominant-negative effect by forming nonfunctional heterodimers with wild-type HFE, though the primary mechanism is haploinsufficiency.
View complete mutation data：
Gene Ontology (GO)
| • protein binding (GO:0005515) | • plasma membrane (GO:0005886) |
| • cellular iron ion homeostasis (GO:0006879) | • integral component of membrane (GO:0016021) |
| • transferrin receptor binding (GO:0033572) | • intracellular organelle (GO:0043229) |
| • iron ion homeostasis (GO:0055072) |
Pathways
• Iron uptake and transport (Reactome: R-HSA-917937)
• Hepcidin regulation of iron homeostasis (KEGG: hsa04978)
• Transferrin receptor recycling (Reactome: R-HSA-917977)
Protein Summary
The HFE protein (UniProt Q30201) is a 343-amino acid type I transmembrane glycoprotein that localizes to the plasma membrane. It associates with beta-2 microglobulin and binds to transferrin receptor 1 (TFRC), modulating cellular iron uptake. In the liver, HFE signaling upregulates hepcidin (HAMP) expression, which controls systemic iron levels. Loss of HFE function leads to hepcidin deficiency, increased ferroportin activity, and iron overload characteristic of hereditary hemochromatosis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HFE Knockout HEK293 Cell Line | EDJ-KQ1908 | Human | 3077 | Details Get a Quote |
| ADHFE1 Knockout HEK293 Cell Line | EDJ-KQ9397 | Human | 137872 | Details Get a Quote |
| ADHFE1 Knockout HCT 116 Cell Line | EDJ-KQ36045 | Human | 137872 | Details Get a Quote |
| HFE Knockout A-549 Cell Line | EDJ-KQ21818 | Human | 3077 | Details Get a Quote |
| HFE Knockout HCT 116 Cell Line | EDJ-KQ21819 | Human | 3077 | Details Get a Quote |
| HFE Knockout HeLa Cell Line | EDJ-KQ21820 | Human | 3077 | Details Get a Quote |
| ADHFE1 Knockout HeLa Cell Line | EDJ-KQ58379 | Human | 137872 | Details Get a Quote |
| ADHFE1 Knockout A-549 Cell Line | EDJ-KQ66867 | Human | 137872 | Details Get a Quote |
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