The Hemochromatosis Gene

Official Gene Symbol: HFEAlternate Symbol: HLA-H

Name of Gene Product: hereditary hemochromatosis protein

Locus: 6p21.3 The HFE gene is found in region 21.3 on the short (p) arm of human chromosome 6.

Size: The HFE gene’s 7 coding regions (exons) are scattered over about 10,000 base pairs of genomic DNA. Exons translated into the HFE protein are interspersed with segments of noncoding DNA (introns). After transcription, introns are spliced out and exons are pieced together to form an mRNA transcript about 2700 bp long. The mRNA is then translated into the 348-amino acid sequence of the hereditary hemochromatosis protein [1,2,3]. Mutations in the HFE gene can result in hereditary hemochromatosis (HH).

Protein Function

The HFE protein is a transmembrane protein expressed in intestinal and liver cells; it works in conjunction with another small protein called beta-2-microglobulin to regulate iron uptake [4]. Although homologous to other major histocompatibility complex (MHC) class I proteins that present antigens to killer T cells, the HFE protein appears to have no immunological function [5]. The HFE protein is an interesting example of how homology is not always an indicator of protein function.

Sequence ExerciseThe “mRNA” sequences obtained from databases such as NCBI’s GenBank are actually complementary DNA (cDNA) sequences generated from mRNA transcripts extracted from cells. Genomic DNA sequences of eukaryotic organisms contain coding segments (exons) interspersed with noncoding segments (introns). During transcription, introns are spliced out and exons are pieced together to form messenger RNA (mRNA). In addition to containing nucleotides that are translated into the amino acid sequence of a particular protein, mRNA also contains untranslated regions upstream and downstream of the coding sequence. Intron-free cDNA sequences synthesized from mRNA also comprise these untranslated regions.

Use the Table of Standard Genetic Code to find the initiation codon (ATG) and next nine codons in the HFE nucleotide sequence shown below. The first 10 amino acids of the hereditary hemochromatosis (HH) protein sequence are as follows:


1 ggggacactg gatcacctag tgtttcacaa gcaggtacct tctgctgtag gagagagaga
61 actaaagttc tgaaagacct gttgcttttc accaggaagt tttactgggc atctcctgag
121 cctaggcaat agctgtaggg tgacttctgg agccatcccc gtttccccgc cccccaaaag
181 aagcggagat ttaacgggga cgtgcggcca gagctgggga aatgggcccg cgagccaggc
241 cggcgcttct cctcctgatg cttttgcaga ccgcggtcct gcaggggcgc ttgctgcgt

Nucleotide sequence taken from NCBI RefSeq record NM_000410

The answer is at the bottom of this page.

Protein StructureHFE protein consists of extracellular alpha-1 and alpha-2 domains that sit on top of the immunoglobulin-like alpha-3 domain, which spans the cell membrane and binds a separate protein called beta-2-microglobulin. The alpha-1 and apha-2 domains interact with the transferrin receptor, another transmembrane protein that plays a very important role in iron uptake and regulation [6].
Figure 1: Two Hfe (Human) Hemochromatosis Protein Molecules.
Source: PDB ID 1A6Z as viewed in Protein Explorer

Figure 1 shows backbone structures of two HFE protein molecules. Blue and green chains represent HFE proteins, and smaller aqua and gold chains represent molecules of beta-2 microglobulin. Purple residues indicate where cysteine 282 is located in each HFE chain. A mutation at cysteine 282 is a common cause of hereditary hemochromatosis.

Common Disease-Causing Mutation

The most common mutation responsible for hereditary hemochromatosis is the substitution of tyrosine for cysteine at the 282nd amino acid position in the protein sequence (C282Y mutation). The cysteine residue at this position is part of a disulfide bond that forms a loop in the alpha-3 domain of the HFE protein.When cysteine 282 is lost, the disulfide bond cannot be formed and the HFE protein’s alpha-3 domain is no longer able to complex with beta-2-microglobulin, which serves as a stabilization factor. As a result, the mutated HFE protein is degraded before it has a chance to be incorporated into the cell membrane.

Cells become iron-overloaded when there is no HFE to negatively regulate the iron flow into the cell’s cytoplasm [4]. Over time, iron overload in these cells can damage tissues and organs, leading to symptoms and complications associated with HH.

Additional Resources
HFE Records from Different Bioinformatics Databases

OMIM Entry for HFE (MIM no. 235200)

NCBI LocusLink Entry for HFE

GeneCard for HFE

Genome Database Entry for HFE

HFE Nucleotide Sequence

NCBI mRNA Reference Sequence NM_000410

NCBI Genomic Nucleotide Sequence from GenBank Z92910

HFE Protein Sequence

NCBI Protein Reference Sequence NP_000401

HFE Protein Structure

1A6Z – Protein Data Bank entry for the Crystal Structure of HFE (Human) Hemochromatosis Protein

1DE4 – Protein Data Bank entry for the Crystal Structure of Human Hemochromatosis Protein HFE Complexed with Transferrin Receptor

HFE Mutation Resources

Human Gene Mutation Database Entry for HFE

Other HFE Web resources

“HFE Gene and Hereditary Hemochromatosis” – Review created by HuGE Net (Human Genome Epidemiology Network) at the Centers for Disease Control and Prevention (CDC). It was also published in the American Journal of Epidemiology 154 (3):193-206 (2001).

“Hemochromatosis: A ‘Simple’ Genetic Trait” – This online publication in Hospital Practice provides an excellent overview of the hemochromatosis gene, protein function (with detailed illustrations), major and minor mutations, and dilemmas associated with screening for the genetic disorder.

Article Reporting HFE Gene Discovery

J. N. Feder et al. “A Novel MHC Class I-like Gene is Mutated in Patients with Hereditary Haemochromatosis.” Natural Genetics 13 (4): 399-408 (Aug. 1996). PMID 8696333.


  1. “NM_000410: Homo sapiens Hemochromatosis (HFE), mRNA,” in NCBI RefSeq [database online] (Bethesda, MD: NCBI 2001, accessed February 2002), identifier no. NM_000410.
  2. “Z92910: Homo sapiens HFE Gene,” in NCBI GenBank [database online] (Bethesda, MD: NCBI 2001, accessed February 2002), identifier no. Z92910.
  3. “NP_000401: Hemochromatosis; Haemochromatosis [Homo sapiens],” in NCBI RefSeq [database online] (Bethesda, MD: NCBI 2001, accessed February 2002), identifier no. NP_000401.
  4. R. D. Press. “Hemochromatosis: A ‘Simple’ Genetic Trait.” Hospital Practice (1999, accessed February 2002) <>
  5. H. Drakesmith and A. Townsend. “The Structure and Function of HFE.” BioEssays 22: 595-98 (2000).
  6. M. J. Bennett, J. A. Lebron, and P. J. Bjorkman. “Crystal Structure of the Hereditary Haemochromatosis Protein HFE Complexed with Transferrin Receptor.” Nature 403: 46-53 (2000)