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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. |
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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