Hemochromatosis 2012

From Bioinformatikpedia


Hereditary hemochromatosis is an autosomal recessive monogenetic metabolic disease caused by mutations in the HFE gene. Malfunction of the HFE gene leads to an increased absorption of iron in the intestines. Hereditary hemochromatosis was first described in a diabetes report by Armand Trousseau in 1865.

The high iron concentration within the body can cause several side-effects such as arthritis, diabetes, heart muscle disorders, hepatic cirrhosis, hyperpigmentation, and hypopituitarism. The accumulation of iron is a slow process and therefore most patients begin to show symptoms between the age of 30 and 60.

Although this site focuses on hereditary hemochromatosis (hemochromatosis type 1) it is worth noting, that there are differrent types of hemochromatosis.

  • Hereditary hemochromatosis (type 1) - autosomal recessive; gene: HFE
  • Juvenile hemochromatosis (type 2A and type 2B) - autosomal recessive; genes: HJV (2A) / HAMP (2B)
  • Hemochromatosis type 3 - autosomal recessive; gene: TFR2
  • Hemochromatosis type 4 - autosomal dominant; gene: SLC40A1



Hereditary hemochromatosis is quite common, especially in groups with european ancestry. It has a prevalence of about 2 to 3 in 1000 and a carrier rate of about 10 percent.


Hereditary hemochromatosis leads to an unregulated absorption of dietary iron. Due to the increased concentration of iron within the body other dysfunctions can occur depending on the tissue.

  • The accumulation of iron causes a brown coloring of the skin (hyperpigmentation). This can be seen especially well in the armpits, but also on internal organs such as the liver.
  • Iron deposits in the joints may lead to arthritis.
  • A high concentration of iron in the pituitary gland decreases the secretion of hormones (hypopituitarism). This may cause further effects like testicle dysfunction and the loss of sex drive.
  • Regarding the liver it may lead to liver cirrhosis, within the heart to heart muscle disorders (cardiomyopathy).
  • Iron also aids the creation of free radicals which may damage the DNA and cause cancer.
  • In the blood iron competes with chromium for the binding to transferrin. Chromium is important for the normal function of insulin. This disturbance of chromium (due to too much iron) may lead to diabetes.

Men show these symptoms more often than women. This is due to the loss of blood (and iron) during menstruation and pregnancy. The rate of iron accumulation also depends on the patient's diet. Most patients begin to show symptoms between the age of 30 and 60.


See also description of this disease in:

HFE Gene

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Figure 1: Homo sapiens chromosome 6 with marked HFE gene locus (source: genecards)


The HFE gene is located on the short arm of the sixth chromosome (cf. <xr id="fig1"/>). It has a length of 11,124 bases and lies on the plus strand. It further contains six exons, coding for the protein, with a length of 1047 bases.

HFE protein

The protein coded by the HFE gene consists of 4 chains, with 2 different entities in total, the HFE chain and the Beta-2-Microglobulin chain. The conformation of HFE itself can be seen in <xr id="fig2"/>, in complex with Transferrin in <xr id="fig3"/>.

HFE chain

The HFE chain of the protein consists of 8 helices, encoded by 70 residues, and 20 strands, coded by 109 residues.


The Beta-2-Microglobulin chain consists of 11 strands, which are encoded by 51 residues.

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Figure 2: HFE protein (source: PDB)


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Figure 3: HFE-Transferrin complex (source: PDB)



Biochemical disease mechanism

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Figure 4: Iron absorption pathway (source). See figure for a detailed description.


Under normal circumstances, iron is absorbed in the intestines and bound to transferrin (cf. <xr id="fig4"/>). This iron loaded transferrin then associates with the transferrin receptor (TFRC) for further transport through the body. HFE forms a complex with TFRC to reduce its affinity for iron-loaded transferrin and to partially inhibit the release of the iron once the complex reaches the target cells. Further it seems that HFE plays a role in a sensory pathway to determine the iron concentration within the body and to regulate the absorption of iron through the expression of DMT1 (divalent metal transporter).

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Figure 5: HFE mutation effects (source). See figure for a detailed description.


The different mutations in the HFE gene diminish or inhibit these functions (cf. <xr id="fig5"/>). C282Y affects the beta-2-microglobulin binding site and prevents the formation of the HFE-TFRC-complex. H63D does not prevent the formation of the complex, however reduces the inhibitory functions of HFE. This causes the increased iron uptake and accumulation of iron within the cells which is associated with hereditary hemochromatosis.

Dysfunctional HFE seems to also lead to a lack of hepcidin, another protein that (down-)regulates the iron uptake.




As hereditary hemochromatosis is an autosomal recessive disease, the genes on both chromosomes have to be affected by a mutation/mutations to lead to an outbreak of the disease. This can be through homozygosity or compound heterozygosity. However, in 30-50% of the cases the patients didn't show any symptoms of an iron overload.

The most common genotypes for hemochromatosis are:

  • C282Y homozygosity
  • C282Y/H63D compound heterozygosity
  • H63D homozygosity.

Reference sequence

KEGG lists the following sequence for the HFE protein:


This protein has a length of 348 amino acids and the red positions indicate the positions of known mutations, associated with hemochromatosis.

Disease causing mutations

Arg-Ser 6
Val Met 53
Val-Met 59
His-His 63
His-Asp 63
Ser-Cys 65
Arg-Term 71
Gly-Arg 93
Ile-Thr 105
Gln-His 127
Glu-Gln 168
Glu-Term 168
Trp-Term 169
Ala-Val 176
Leu-Pro 183
Arg-Gln 224
Val-Leu 272
Cys-Tyr 282
Cys-Ser 282
Gln-Pro 283
Val-Ala 295
Arg-Met 330
the mutations are listed as fromAA-toAA atPosition#


22 bp cd 50 nt.370 (described at genomic DNA level)
32744 bp incl. entire gene [Alu mediated] (described at genomic DNA level)



Disease causing splicings

IVS2 ds +4 T-C
IVS3 ds +1 G-T
IVS5 ds +1 G-A

Complex rearrangements

c.[128G>A;187C>G], p.[G43D;H63D]




Diagnosis of hereditary hemochromatosis can be achieved by multiple methods.

  • Blood test: Measurement of the transferrin saturation or the serum ferritin concentration in the blood. Values that are significantly above the normal levels can be an indicator for hemochromatosis.
  • Liver biopsy: Extraction and examination of liver tissue. A high concentration of iron within the liver corresponds to a high concentration of iron in the body.
  • MRI: Magnetic resonance imaging can also be used to determine the iron concentration within the liver.

If these methods show a risk for hemochromatosis, a genetic analysis for the known HFE mutations is recommended.



Hemochromatosis itself cannot be treated, but the symptoms can be prevented or lessened.

  • Phlebotomy: Bloodletting can be used to decrease the iron concentration. About 500ml of blood are extracted once a week until the iron concentration reaches a normal level. The extractions should then be repeated every two to three months.
  • Drugs: If the patient can’t handle frequent blood loss, chelating agents can be used in order to bind the iron in the blood and increase its excretion through feces and urine. Examples are deferoxamine, deferasirox, and deferiprone.
  • Diet: Reducing the consumption of iron rich food decreases the rate of iron accumulation and therefore the development of the symptoms. It is also helpful to avoid the consumption of vitamin C about two hours before or after meals, because vitamin C assists the absorption of iron. Alcohol should also be avoided.

All of these treatments have to be continued throughout life to keep the iron concentration within normal levels.



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