Overview Of Hereditary Haemochromatosis Biology Essay

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Hereditary Haemochromatosis also called genetic haemochromatosis, is a genetically determined disorder in which mutations of certain genes involved in iron metabolism can cause increased intestinal iron absorption (Pietrangelo 2006). The general phenotype of Haemochromatosis is progressive iron accumulation in tissues such as the liver, pancreas and heart cells as well as a raised serum transferrin saturation and ferritin concentration (Janssen and Swinkels 2009).

Following the saturation of iron stores, the excess iron deposits within the parenchymal cells of the liver (predominantly), pancreas, pituitary, synovium, heart, and elsewhere (Fowler 2008). The excess free iron participates in intracellular redox reactions ultimately contribution to the generation of reactive oxygen species, causing cell damage or death. As the build up of iron occurs slowly over many years, most patients do not present with symptoms until middle age.

Hereditary Hemochromatosis is one of the most common autosomal recessive disorders among Caucasians in the United States however, only a small proportion of these people suffer any symptoms. This seems be attributable to both environmental (diet and blood loss) as well as genetic factors. Recent advances in the development of animal models that show the complications of hemochromatosis may soon provide useful tools in deciphering how other genes play a part in iron regulation.

The development of HH is often related to the presence of C282Y, H63D and/or S65C mutations in the gene that expresses the protein HFE (Martinelli et al., 2005 (Oliveira et al., 2006), whose activity is to regulate the intestinal absorption of iron (Bittencourt et al, 2002). C282Y and H63D mutations are known as the main ones responsible for HH (Guer­reiro et al., 2006; Ferreira et al., 2008).

Clinical Presentation and Phenotypic Expression

It is now quite rare to see the classic triad of bronzed skin, diabetes and cirrhosis, probably because of earlier diagnosis and management.

Generally, HH appears between 40 to 60 years old, an age at which there is an excess of 20 to 40 g iron, accumulated slowly in the body throughout life (Pedersen et al., 2008), where the fifth decade is the most common age for the main signs and symptoms in women (US Preventive Services Task Force, 2006).

The most common symptoms of HH are subjective and nonspecific, such as fatigue, lethargy and arthralgia. Symptoms are caused by this excess iron being deposited in multiple organs of the body primarily affecting the hepatic, endocrine or cardiac organs. In cases of significant iron overload, individuals may present with organ specific symptoms such as those related to chronic liver disease. Arthralgia or arthritis related to haemochromatosis typically involves the second and third metacarpo-phalangeal joints. Endocrine dysfunction can take the form of diabetes due to iron deposits in the pancreas and iron deposits in the gonads leading to hypogonadism. Occasionally the patient may present with symptoms related to cardiomyopathy, either with symptomatic cardiac failure or arrhythmias.

The percentage breakdown of symptoms is estimated to include (60%) weakness, (30%), arthralgia, (40%), arthritis, (13-60%) hepatomegaly/cirrhosis, (5%) hepatocarcinoma, (0-30%) Diabetes Mellitus, (0-40%) sexual dysfunction, (20% females - 29% males), arryhtmiaa and cardiac failure (15% females - 35% males). Excess iron in the liver causes cirrhosis, which may develop into liver cancer. Similarly, excess iron stores can cause cardiomyopathy occasionally presenting with either symptomatic cardiac failure or arrhythmias.


Hereditary haemochromatosis (HH) is one of the most common inherited disorders, with a frequency of 0.4-1.0% in people of Northern European origin. According to a Hemochromatosis and Iron Overload Screening known as the (HEIRS) study in North America, a study was conducted on a multiethnic population of 101 168 participants. The findings showed that one in 227 white people were homozygotes for the HFE C282Y mutation, a genotype seen in more than 90% of patients with typical haemochromatosis. Although C282Y homozygosity is common in most northwestern European countries (and also in Portugal), the highest reported prevalence for C282Y homozygosity is one in 83 in Ireland. One theory is that the C282Y mutation in the HFE gene originated in central Europe around 4000 BC. The migration of Europeans to USA, Canada, South Africa, and Australia accounts for the high prevalence of haemochromatosis in white individuals in these countries. In Ireland an allele frequency of 12.3% for C282Y and 12.6% H63D has been found with 19.7% heterozygotes for C282Y, 19.3% heterozygous for H63D, 2.1% homozygous for C282Y, 2.7% homozygous for H63D and 0.5% compound heterozygotes.

It is possible the high levels of HFE mutations in Celtic populations have been maintained because they confer a selective advantage in the prevention of iron deficiency. Although some of these people might have forms of iron overload, the most common reasons for increases of serum ferritin in large populations include inflammation, obesity, alcohol consumption, and other disorders. Thus, increases in transferrin saturation and serum ferritin are not always caused by iron overload. A diagnosis of haemochromatosis based on iron overload might seem straightforward, but a growing number of iron-overload diseases exist, and they do not share the same pathophysiological changes, prognosis, or response to therapy. A case definition based on the HFE C282Y genetic test includes asymptomatic people who might never develop iron overload. A large, middle-aged, population based study from Melbourne, reported an incidence of C282Y homozygosity of 0.68% and compound heterozygosity (C282Y/H63D) of 2.4%.(Clark P 2010) These rates are similar to studies of white North American populations. In practice, physicians use clinical judgment, iron tests, and genetic testing to understand the cause of iron overload and to guide their approach to treatment

Classification of Hereditary Haemochromatosis

Figure 1. (Janseen M.C.H 2009)shows the various causes of iron overload in humans. Very rare types of hereditary haemochromatosis Types V and VI are not shown but are described below along with Types 1-IV.

The nomenclature of haemochromatosis is controversial. Haemochromatosis indicates the disease that results from iron loading; thus the term refers to the clinical complications due to iron toxicity in different organs, mainly the liver. The most common form, the first to be recognized, is HFE-related. According to On Line

Mendelian Inheritance in Man (http://www.ncbi.nil.nih.gov/entrez/query.fcgi?dbZ

OMIM), this classic form is called simply haemochromatosis or HFE-related

haemochromatosis. The term HFE refers to the responsible HLA class I-like gene

that in the original paper was called HLA-H.1 The other forms of haemochromatosis are defined by numbers (type 2, type 3 and type 4), with an order that reflects their chronological recognition. Type 2 is also called 'juvenile haemochromatosis' (JH), since its distinctive feature is the early onset of clinical complications. Type 2 is by itself heterogeneous, since it can result from mutations in two different genes: more commonly (type 2A) HJV, encoding hemojuvelin7, and in a rare subset of patients (type 2B) HAMP, encoding hepcidin. Type 3 haemochromatosis is characterized by TFR2 mutations11 and shows intermediate clinical features between classic type (HFE related) and type 2. Finally, type 4 is a separate disorder due to mutations of SCL40A1, which encodes the iron exporter ferroportin It is also called 'ferroportin disease' since its genetic, biochemical, clinical and histological features are distinct from haemochromatosis. A genetic classification of the different forms is reported in Table 1. The new term for each disorder could be HFE-related haemochromatosis, TFR2-related haemochromatosis, hepcidin- or hemojuvelin-related haemochromatosis, and ferroportin disease, respectively.

Presently the most common categorisation is according to OMIM and 6 types of hereditary Haemochromatosis have been identified.

Type 1 HFE associated Haemochromatosis often known as classical Haemochromatosis is the most common form and is an autosomal recessive disorder of low penetrance. It is strongly associated with mutations on the HFE gene on chromosome 6 (p21.3). It is most common in populations of northern European extraction in whom approximately one in ten are heterozygous carriers and 0.3-0.5% ar homozygous for the C282Y mutation in HFE.

Type 2 Juvenile Haemochromatosis is an autosomal resessive disorder of high penetrance with causative mutations identified in the HFE2 gene on Chromosome 1 (q21) and with the HAMP gene on chromosome 19(q13).

Type 3 Transferrin Receptor 2 mutations is an autosomal recessive with mutations in the TfR2 gene on chromosome 3(7q22).

Type 4 Haemochromatosis (Ferroportin Disease) is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene also known as SLC40A1. It is a variable disorder. Some families have high ferritin levels, increased macrophage iron, reduced transferrin saturation, mild anaemia and minimal iron deposition ("(Ferroportin disease"). Other families have findings similar to classical HH.

Type 5 H-Ferritin Mutations is an autosomal dominant disorder found in four to seven members in single Japanese family. The genetic defect is in H-ferritin.

Type VI Hereditary Hyperferritinaemia - Cataract Syndrome (HH-CS) is an autosomal dominant disorder. The genetic defect is in L-ferritin. The phenotype typically involves high levels of ferritin in association with bilateral congenital cataract without iron deposition.



1-2mg of iron is absorbed by the normal individual which is balanced by equivalent losses. In normal subjects there is no mechanism to regulate iron loss from the body, which averages about 1mg/day in adult men from sweat, shed skin and gastrointestinal losses. Therefore to ensure normal stores of iron within the body absorption must be tightly regulated.

1-2 mg of iron is absorbed by the normal individual which is balanced by equivalent losses. Most of the iron utilised in the body is recycled from senescent erythrocytes by macrophages, and returned to the bone marrow for incorporation in erythroid precursors. The major iron stores are in the liver and reticuloendothelial cells. The liver produced peptide hepcidin controls the plasma iron concentration by inhibiting iron export by ferroportin from enterocytes and macrophages. This means that an increased production of hepcidin leads to a decrease in plasma iron concentrations. Hepcidin expression is regulated by body iron stores, erythroid iron demand, inflammation, and hypoxia via regulation pathways involving expression of HFE, Tfr2 TfR1 and HJV genes.

(Janseen M.C.H 2009)


Iron homeostasis is regulated strictly at the level of intestinal absorption and release of iron from macrophages.

Intestinal iron absorption - The gastrointestinal mucosa plays a major role in regulating iron absorption, which varies according to the form of iron in the diet [120]. A Western daily diet contains about 15 mg of iron. Some of this is heme iron, of which about 30 percent is promptly absorbed, likely via its own transport system. A candidate heme iron transporter, named heme carrier protein 1, has been found in the apical brush border membrane of duodenal enterocytes in the mouse [121].

The remaining iron, accounting for almost all of the iron in the diet in non-Western countries, is poorly absorbed, with less than 10 percent being taken into the mucosal cells (algorithm 2).

Heme dietary sources (fish, poultry, and meat) have a higher bioavailability than do non-heme (vegetable) sources (30 versus 10 percent). In addition, intraluminal factors can affect absorption (table 1). Ascorbic acid enhances the absorption of non-animal sources of iron such as cereal, breads, fruits, and vegetables, whereas tannates (teas), bran foods rich in phosphates, and phytates inhibit iron absorption [122-124].

Molecular mechanisms of intestinal heme absorption are unclear. A heme carrier protein has been proposed, which is highly expressed in the gut and stimulated by hypoxia [121]. This carrier, Feline Leukemia Virus Receptor 5 (FLVR5) is expressed in enterocytes, macrophages and erythroblasts with the likely function of exporting heme excess [67]. (See 'Heme exporter' above.)

Iron in food is prominently ferric (Fe3+), which is poorly soluble above a pH of 3 and is therefore poorly absorbed. In comparison, ferrous iron (Fe2+) is more soluble, even at the pH of seven to eight seen in the duodenum. As a result, it is more easily absorbed.

Ferrous iron is taken up at the mucosal side by the intestinal transporter, DMT1 [125]. In this process duodenal cytochrome b provides reduction of ferric to ferrous iron. The iron is thought to enter the cell where it binds to cytosolic low molecular weight iron carriers and is transported to the basolateral portion of the cell. To enter the circulation, iron must be transported across the basolateral membrane by the duodenal iron exporter, ferroportin. Upon its release, the ferrous iron is oxidized to the ferric form, and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of ceruloplasmin, a known ferroxidase.

Transferrin (Tf)

Transferrin receptor (TfR)

Ferritin (Ft)

Iron regulatory protein 1 and 2 (IRP1 and IRP2), the cellular iron sensing proteins

Divalent metal transporter 1 (DMT1, Nramp2, DCT1, Solute carrier family 11, member 2 (Slc11a2)), the duodenal iron transporter

Ferroportin (Ireg1, SlC40A1, Mtp1),functions as a major exporter of iron, transporting iron from mother to fetus, transferring absorbed iron from enterocytes into the circulation, and allowing macrophages to recycle iron from damaged red cells back into the circulation.

Hephaestin, which likely cooperates with ferroportin for exporting iron to transferrin.

HFE, mutations of which are responsible for the common form of hereditary hemochromatosis

TFR2, mutations of which are responsible for a rare form of hereditary hemochromatosis

Hemojuvelin, a hepcidin regulator, mutations of which are responsible for the common form of juvenile hemochromatosis

Hepcidin, the key negative regulator of intestinal iron absorption as well as macrophage iron release. Mutations of hepcidin cause a rare form of juvenile hemochromatosis [4].

In hereditary haemochromatosis (HH) patients can absorb 3-4mg/day resulting in an increase of 0.4/1g/year. If iron absorption is increased by as little as 1.5mg/day above the amount needed to achieve homeostasis, this will result in the accumulation of 5.5 grams of iron every decade, 16 grams in 30 years and 33 grams in 60 years. This later fiqure corresponds to the amount of iron (30 to 40g) usually found in patients with clinically detected hereditary haemochromatosis. Due to menstruation and preg­nancy, HH occurs 2 to 4 times more in men than in women (Limdi and Crampton, 2004; US Preventive Services Task Force, 2006).

IRON TOXICITY - The iron replete state is characterized by increased production of ferritin to permit adequate storage along with decreased production of the transferrin receptor to minimize further iron entry into the cell. These responses are mediated by the iron responsive element binding protein (IRE-BP)

The expression of proteins involved in cellular iron uptake and storage is regulated by the iron status of the cell. Iron-regulatory proteins 1 and 2 (IRP1 and IRP2) are cytosolic RNA-binding proteins that bind to iron-responsive elements (IRE), consisting of a loop configuration of nucleotides, that are located in the 5'- or 3'-untranslated regions (UTR) of specific mRNAs encoding for iron genes (eg, ferritin, TfR, DMT1, ferroportin and the erythroid specific form of delta-aminolevulinic acid synthase (eALAS)) [31].

Binding of IRPs to their target sequences occurs when the cell is iron deficient and has different effects according to whether the IRE position is at the 5' or the 3' UTR, as follows:

When IRPs bind to the 5' IRE of ferritin or eALAS, the rates of biosynthesis are decreased

When IRPs bind to the 3' end of transcripts such as TfR or DMT1, the mRNA half-life is prolonged and rates of biosynthesis are increased (algorithm 1) [31].

IRP1 and IRP2 sense the state of the iron balance in the cell in different ways. When cellular iron levels increase, assembly with iron sulfur clusters changes IRP1 aconitase and its binding ability is lost. Under the same conditions of cellular iron increase, IRP2 is degraded by the proteasome [32,33].

The net effect is that the iron overloaded state is characterized by increased production of ferritin (to permit adequate storage) and decreased production of TfR (to minimize iron uptake). These changes are reversed in iron deficiency, which is characterized by reduced ferritin and elevated TfR synthesis (algorithm 1), upper left and upper right, respectively) [1,2].

As the body content (burden) of iron increases, the saturation of circulating transferrin with iron increases, resulting in the production of increased amounts of nontransferrin bound iron (labile plasma iron) [4,5], and the off-loading of iron, especially to cells with high levels of transferrin receptors (eg, heart, liver, thyroid, gonads, and pancreatic islets), resulting in such complications as cardiomyopathy, cirrhosis, endocrinopathy, and diabetes.

The excess iron in these cells may act as a Fenton agent, catalyzing the Haber-Weiss reactions [6]:

           H2O2  +  Fe(2+)   ->   OH-  +  Fe(3+)  +  OH• (hydroxyl radical)

           O2- (superoxide anion)  +  Fe (3+)   ->   O2  +  Fe(2+)

           SUM: H2O2  +  O2-   ->   O2  +  OH-  +  OH•

The reactive oxygen species produced by these reactions presumably oxidize lipids, proteins, and perhaps RNA and DNA, thereby causing tissue damage and subsequently fibrosis


The methods used to establish the presence of iron overload (increased body iron burden) include serum iron studies, various radiologic techniques, liver biopsy, and assessment of the response to phlebotomy or chelation therapy [15] Increased suspicion of iron overload can also come from a positive family history for iron overload and/or HH [16].

CT, MRI, and SQUID techniques 

- The DEFINITIVE TEST for the diagnosis of hepatic iron overload and its consequences (eg, cirrhosis, hepatocellular carcinoma) is liver biopsy (see below), although noninvasive imaging studies, such as CT as well as T2* and R2* measurements by MRI have become increasingly accurate for determining both hepatic as well as cardiac iron deposition

Measurement of hepatic iron concentration as determined by magnetic susceptometry using a Superconducting Quantum Interference Device (SQUID) yields results that are quantitatively equivalent to those obtained by chemical analysis of liver biopsy tissue [47,48]. However, because of their complexity, expense, and requirement for liquid helium cooling, only about four instruments are available worldwide for clinical use.

Liver biopsy Quantitative phlebotomy, as described below, is an alternative method for determining the presence or absence of iron overload in non-anemic patients, such as those with hereditary hemochromatosis

liver biopsy, quantitative phlebotomy and imaging techniques provide no information about the cellular location of the removed iron, or the presence or absence of hepatic fibrosis, cirrhosis, or hepatocellular carcinoma, important complications of iron overload. Parenchymal iron loading can be demonstrated by Perls' Prussian blue staining of a liver biopsy specimen, while standard histologic examination can detect the presence of fibrosisThe hepatic iron content is preferably reported as micromoles of iron per gram dry weight of liver. Normal values are <36 micromol/g, while values >71 micromol/g are highly suggestive of homozygous HH [50]. This value can be divided by the subject's age in years to give the hepatic iron index (HII); a value ≥1.9 is consistent with, but not diagnostic of homozygous

Serum Indices of Iron Stores

Plasma (or serum) iron concentration - normal 60 to 150 microg/dL.

Transferrin concentration (plasma total iron binding capacity, TIBC) - normal 300 to 360 microg/dL. The ratio of plasma iron to transferrin permits calculation of the transferrin saturation - normal 20 to 50 percent.

Plasma ferritin - normal 40 to 200 ng/mL (microg/L)

The appropriate interpretation of transferrin saturation and serum ferritin results is essential in the diagnosis of iron overload. Fasting transferrin saturation (the ratio of serum iron to total iron binding capacity) is the most sensitive initial phenotypic screening test (see Figure).4 A cut-off value of ≥45% will detect almost all affected C282Y homozygotes. A fasting morning sample is recommended as serum iron levels may be misleadingly elevated in the postprandial state

and also by circadian rhythm. However one large study has suggested that the use of fasting transferrin saturation had no advantage over the use of random samples in a primary care

population.Unsaturated iron binding capacity has also been used and is a valid alternative to transferrin saturation. Serum ferritin reflects body iron stores and generally rises later

in the progression of iron overload. Iron overload increases the hepatic production and release of ferritin. Interestingly, the role of ferritin in the blood remains unclear. There are a number of confounding causes of hyperferritinaemia that warrant consideration. These include alcohol abuse, the metabolic syndrome, inflammatory states and acute or chronic hepatitis. In the absence of these conditions, serum ferritin is a good marker of the degree of iron overload. High serum ferritin levels greater than 1000 μg/L indicate a greater risk of cirrhosis or advanced fibrosis and have been used, irrespective of age and transaminase levels, as an indication for liver

biopsy.10 The negative predictive value of a normal transferrin saturation and serum ferritin is 97%. In this situation, no further testing is recommended.

A fasting transferrin saturation ≥60 percent in men or ≥50 percent in women has been accurate in detecting over 90 percent of patients with homozygous HH who have clinical symptoms and/or documented iron overload. However, many investigators have advocated using a lower "cutoff" value of 45 percent transferrin saturation for both men and women, which will lead to fewer patients being missed (ie, those with the disease but without symptoms and/or iron overload), at the expense of an increased false positive rate.

Increased iron also stimulates the hepatic production and release of ferritin [21]. As a result, a plasma ferritin concentration above 300 ng/mL in men and 200 ng/mL in women provides further support for the diagnosis of iron overload.

Even as researchers and laboratorians debate the merits of various iron status biomarkers, they are in agreement that development of robust and reliable commercial hepcidin assays could transform the diagnostic landscape. "The field is moving to hepcidin. It may be as popular in three to five years as ferritin is now," predicted Thomas. However, he cautioned that values reported by immunoassay and mass spectrometry methods vary considerably. A recent review article bore this out: the seven methods examined used a wide range of normal values and had variable intra-assay precision and lower limits of detection (J Prot 2009 doi:10.1916/j.jprot.2009.08.003). Meanwhile, Dutch researchers have proposed an algorithm using transferrin saturation, sTfR and CRP to predict measured hepcidin levels (Blood Cells Mol Dis 2008;40:339-346).

HFE Gene Mutation Testing

Many mutations in the body's iron transport system can cause hemochromatosis; however, most cases are caused by mutations in the HFE gene. This is located on chromosome 6, and one mutation leads to the substitution of the 282nd amino acid in which Cysteine becomes tyrosine, therefore the mutation is called C282Y.

The switch of amino acids is thought to affect how the HFE protein interacts with the transferrin receptor (TFR1), which plays an important role in iron homeostasis. A less common mutation, H63D, has also been identified in the HFE gene

The C282Y mutation is a missense mutation that substitutes a cysteine residue for tyrosine at amino acid position 282 on the HFE protein. The other significant mutation is referred to as H63D which results in the substitution of aspartic acid for histidine at amino acid position 63 on the HFE protein. Testing for these mutations is widely available. Those who have one of each mutation are termed compound heterozygotes. Only those who are homozygous for C282Y and compound heterozygotes have the potential to develop significant iron overload related to HFE gene mutations. Testing for HFE gene mutations is generally indicated in those with an iron overload phenotype and those with a family history of HFE-related HH.

The S65C HFE mutation

S65C mutation, recently found to be related to milder HH, comes from an amino acid conversion of serine (S) to cysteine (C) at position 65, due to an adenine (A) to thymine (T) transversion at position 193 of the HFE gene. A number of rare but important forms of non-HFE related HH have also been described.(Clark P 2010)

Type IV Haemochromatosis (Ferroportin disease)

Ferroportin (Fpn) disease/Type IV Haemochromatosis (HH Type IV) OMIM 606069 is a form of iron overload caused by mutations in the SLC40A1 gene encoding Ferroportinn. There are two categories of Ferroportin mutations. The first category known as the Macrophage Phenotype or "M" phenotype is present in most cases of the condition. Subjects with these loss of function mutations present with hyperferritinaemia, macrophage iron deposition, normal transferrin saturation and borderline anaemia with low tolerance to phlebotomy. The loss of function mutations reduce the cell surface localisation of Fpn reducing its ability to export iron. The age of clinical onset for this disease is the 4th- 5th decade of life. Treatment of iron overload in subjects with this type of HH can be problematic because the nature of the underlying disease limits the ability of phlebotomy therapy to mobilise iron stores. The more common M phenotype is caused by mutations that reduce the iron export from macrophages resulting in macrophage accumulation and normal-low transferrin saturation.

The second category or "H" phenotype includes 'gain of function' mutations that do not alter cell surface expression but rather abolish hepcidin-induced fpn internalisations and degradation. Patients develop symptoms similar to classical Haemochromatosis such as elevated transferrin saturation and iron deposition in hepatocytes, the "H" phenotype. Iron distribution is similar to HFE- HH, being primarily parenchymal. Treatment of individuals with this disorder is similar to that for HFE-HH. Some persons have an intermediate phenotype with a mixed pattern of liver iron accumulation. The reported mutations are predicted to alter the physiochemical properties of the protein. According to consensus structural predictions ferroportin has 9-10 transmembrane helices. Although the reported mutations span the whole protein, the majority involve the region between the first and fifth transmembrane domain, this region may be involved in iron binding and/or transport activity. Other mutations may affect a functional binding site for a protein that is important for the export of iron from the cell (caeruloplasmin or hepcidin). The less common H phenotype maybe due to hepcidin-resistant mutations that permit continued export of iron from macrophages and result in disease that resembles HFE associated HH. No definitive evidence of various Fpn mutations has yet been provided.

SLC40A1 gene

The SLC40A1 gene (solute carrier family 40 iron regulated transporter) member 1 is the official name of this gene. The SLC40A1 gene belongs to a family of genes called SLC (solute carriers). A gene family is a group of genes that share important characteristics. SLC40A1 is also known by others names (IREG 1, MTP1, FPN1 and formely SLC11A1. It is loated on chromosome 2(2q 32). It is compromised of 8 exons and introns and has an iron responsive element (IRE) in its 5' untranslated region UTR. Twenty missense mutation of the SLC40A1 gene have been reported in individuals from diverse ethnic groups, The vast majority of these leads to hyperferritinaemia and iron overload although six mutations (HM4, D270, G399D, L384M, R561 there is no clinical or laboratory data. A Q248H mutation appears to be a functional polymorphism with hig incidence in African-Americans which leads to disease in the presence of other modifying factors. The mutational analysis of the SLC40A1 gene has been performed at the genomic level by PCR amplification and direct sequencing of all coding regions and flanking regions usually in 9 PCR reactions. The mutation analysis of the SLC40A1 gene has also been performed at the RNA level using reverse transcriptase. This method however is limited as it may overlook mutations in non coding regions.

The function of ferroportin

The SLC40A1 gene provides instructions for producing the protein ferroportin 1 or ferroportin(fpn). Fpn plays an essential role in the regulation of iron levels in the body. Iron from the diet is absorbed through the walls of the small intestine. Fpn then transports iron from the small intestine into the bloodstream. In the bloodstream the iron binds to another transport protein called transferring that carries it to the tissues and organs of the body. Fpn also transports iron out of specialised cells (called reticuloendothelial cells) that are found in the liver, spleen and bone marrow. The iron balance in the body is regulated by the amount of iron stored and released from these cells. Research suggests that another iron requlatory protein "Hepcidin" controls the amount of Fpn available to transport iron out of cells. Hepcidin binds to fpn1 and causes it to be broken down when the bodies iron supplies are adequate. When the body is lacking iron hepcidin levels drop and more fpn is available to bring iron into the body and release it from storage. Ferroportin functions as a major exporter of iron, transporting iron from mother to fetus, transferring absorbed iron from enterocytes into the circulation, and allowing macrophages to recycle iron from damaged red cells back into the circulation.

In animal and human in vitro models, ferroportin-1 is posttranscriptionally regulated by the amount of available iron, due to the presence of an iron responsive element [56-59]. However, the most important control of ferroportin is posttranscriptional, since ferroportin is downregulated through its interaction with hepcidin (figure 1) [54,57,60,61]. When hepcidin levels increase, hepcidin binds to ferroportin and induces its internalization and lysosomal degradation.


S65C mutation, recently found to be related to milder HH, comes from an amino acid conversion of serine (S) to cysteine (C) at position 65, due to an adenine (A) to thymine (T) transversion at position 193 of the HFE gene. Its frequency in Caucasians is around 0.005 to 0.03 (Cimburová et al., 2005). The Ecuadorian population shows S65C allelic frequency of 0.04, the highest found so far (Oliveira et al., 2006). HH of lesser severity is also associated with the presence of H63D/S65C and C282Y/S65C composed heterozygosity (Cimburová et al 2005; Oliveira et al., 2006).

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Janssen, M. C. and D. W. Swinkels (2009). "Hereditary haemochromatosis." Best Pract Res Clin Gastroenterol 23(2): 171-83.

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