Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis

In the UK, 90% of patients with hereditary haemochromatosis (HH) are homozygous for HFE C282Y, as are one in 150 people in the general population. However, only a minority of these will develop clinical haemochromatosis. Iron loss modifies iron accumulation but so may other genetic factors. Haptoglobin (Hp) exists as three major types (Hp 1-1, Hp 2-1 or Hp 2-2) and binds free plasma haemoglobin. In men, Hp 2-2 has been shown to be associated with increased macrophage iron accumulation and serum ferritin concentration. Furthermore, the frequency of Hp 2-2 was shown to be increased in patients with HH. We determined Hp types by phenotyping and genotyping 265 blood donor control subjects and 173 subjects who were homozygous for HFE C282Y. The latter group included 66 blood donors lacking clinical features suggestive of haemochromatosis and without a known family history, and 68 patients presenting clinically with haemochromatosis. Hp 2-2 frequencies did not differ in control subjects and C282Y homozygotes. Hp 2-2 was not a risk factor for disease development in HH. To investigate the relationship between iron accumulation and haptoglobin type, we determined transferrin saturation and serum ferritin concentration in 192 male, first-time blood donors aged 20-40 years who lacked both HFE C282Y and H63D. Transferrin saturation and serum ferritin concentrations did not vary with Hp type

Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3)

We describe a family with autosomal dominant inheritance of increased body iron stores characterized by raised serum ferritin concentration and normal transferrin saturation. Liver biopsy showed iron deposition in Kupffer cells without fibrosis. The clinical features of HFE-related hemochromatosis were absent, as were the Cys282Tyr and His63Asp mutations. Venesection therapy was poorly tolerated, suggesting a defect in iron release from reticuloendothelial stores. A 3-base pair deletion in exon 5 of the ferroportin 1 gene (SLC11A3) predicting Val162 deletion was found in affected members, but not in unaffected individuals or in 100 control subjects. Consensus structural predictions of the transmembrane helices showed that the deletion is in the extracellular loop between the third and fourth predicted transmembrane helices and lies within a spatial cluster of other known ferroportin 1 mutations. These results indicate that this extracellular cluster is functionally important for iron transport, and its disruption leads to iron overload

HFE mutations, iron deficiency and overload in 10 500 blood donors

People with genetic haemochromatosis (GH) accumulate iron from excessive dietary absorption. In populations of northern European origin, over 90% of patients are homozygous for the C282Y mutation of the HFE gene. While about 1 in 200 people in the general population have this genotype the proportion who develop clinical haemochromatosis is not known. The influence of HFE genotype on iron status was investigated in 10 556 blood donors. The allele frequencies of the C282Y and H63D mutations were

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Rapid genetic screening for haemochromatosis using heteroduplex technology

The recently described association between haemochromatosis and mutations in the HFE or HLA-'H' gene has prompted the need for a simple and rapid genetic test capable of detecting multiple mutations simultaneously. Heteroduplex analysis, a new diagnostic technique, fulfills such criteria and we have investigated the potential for the detection of the Cys282Tyr mutation. 100 subjects were genotyped using the heteroduplex approach. The results showed clear distinction between individuals who did not carry the mutation, individuals who were heterozygous for the mutation and homozygous individuals. Heteroduplex results obtained by both silver staining and capillary electrophoresis showed 100% concordance with those obtained by restriction digestion of PCR product

Thymus-leukaemia antigens: The haemochromatosis gene product?

The gene for hereditary haemochromatosis (HFE) lies telomeric to HLA-A and is believed to be expressed in the intestinal mucosa. Its product has not been characterized, but iron overload and its pathological consequences occur only in homozygotes for this putative gene. The genes encoding the putative human counterparts of the mouse thymus-leukaemia (TL) antigens map to the area where the HFE gene lies. Here, we postulate that a human TL gene may encode a protein acting as or interacting with the transferrin (Tf) receptor in the intestinal mucosa. This hypothesis is based on the following observations: (i) hereditary haemochromatosis (HH) is due to excessive absorption of iron through the intestinal mucosa. HH has a strong association with HLA-A3, but HLA-A3 has no direct role in the pathogenesis and reflects linkage disequilibrium with a telomeric gene. (ii) An HLA-A3 homozygous genotype is associated with the highest relative risks for both early-onset leukaemia and HH. In analogy to the susceptibility locus in mice, this genotype may reflect a TL gene association in leukaemia and raise the possibility of a TL gene involvement in HH. (iii) A TL antigen-like human molecule encoded in the region telomeric to HLA-A, TCA, is expressed in leukaemia and recognized by a Tf receptor-specific monoclonal antibody. The Tf receptor is believed to have a role in the control of intestinal iron absorption. (iv) In mice, particular TL antigens are exclusively expressed in the intestinal mucosa. Therefore, an HLA-A3-linked TL-like molecule, expressed in the intestinal mucosa and sharing a structural similarity with the Tf receptor, may be the yet unknown product of HEE

A new highly polymorphic marker in the 5' untranslated region of HLA-F shows strong allelic association with haemochromatosis

The 5' untranslated region of HLA-F contains a polypurine tract comprising repeats of tri- and hexa-nucleotide motifs. We have recently demonstrated that this polypurine tract is highly polymorphic by using the polymerase chain reaction. Here, we demonstrate that some of the alleles can be explained by a deletion of approximately 100 bp DNA and show that alleles of this novel, highly polymorphic locus are as strongly associated with haemochromatosis as HLA-A3 or D6S105-8. The observed frequency of heterozygosity at HLA-RF is extremely high (95%) and this locus has been found to be informative in pedigrees that are non-informative at HLA-A and D6S105. We also show an example of replication slippage at HLA-F in one pedigre