The Hemochromatosis Gene
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| Approximate gene location is based on Chromosome 6 map from NCBI Entrez Map Viewer. |
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Official Gene Symbol: HFE
Alternate 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).
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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 Exercise
The "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:
M G P R A R P A L L
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.
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Protein Structure
HFE 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].
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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.
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Common Disease-Causing Mutation
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| Firgure 2: Most common HFE mutation that causes HH |
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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.
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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.
References
- "NM_000410: Homo sapiens Hemochromatosis (HFE), mRNA," in NCBI RefSeq [database online] (Bethesda, MD:
NCBI 2001, accessed February 2002), identifier no. NM_000410.
- "Z92910: Homo sapiens HFE Gene," in NCBI GenBank [database online] (Bethesda, MD: NCBI 2001, accessed
February 2002), identifier no. Z92910.
- "NP_000401: Hemochromatosis; Haemochromatosis [Homo sapiens]," in NCBI RefSeq [database online]
(Bethesda, MD: NCBI 2001, accessed February 2002), identifier no. NP_000401.
- R. D. Press. "Hemochromatosis: A 'Simple' Genetic Trait." Hospital Practice (1999, accessed
February 2002) <http://www.hosppract.com/genetics/9908mmc.htm>
- H. Drakesmith and A. Townsend. "The Structure and Function of HFE." BioEssays 22: 595-98
(2000).
- 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)
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