Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homozygosity for the C282Y mutation in the HFE gene is strongly associated with hereditary hemochromatosis. More than one subject out of 10 in the general population is a heterozygote for the C282Y mutation. In this study, we address whether or not conclusions drawn from HLA-based family studies regarding the expression of heterozygous hemochromatosis are applicable to C282Y heterozygotes. The correlation between HLA-inferred and HFE genotypes and the variation of serum iron tests according to HFE genotype and other factors were studied in persons from well-characterized hemochromatosis pedigrees. Subjects were tested for both C282Y and H63D mutations. The following factors were studied: age, sex, alcohol consumption, body mass index, liver function tests, serum lipids and glucose, serum iron, transferrin saturation, and ferritin. HLA-inferred heterozygotes were C282Y heterozygotes in only 70% and compound heterozygotes (i.e., heterozygotes for both C282Y and H63D) in 20%. C282Y heterozygotes did not differ from wild type homozygotes in terms of serum iron tests. Only compound heterozygotes presented with slightly increased transferrin saturation. On the other hand, increased serum ferritin was strongly associated with overweight or lipidic or glucose abnormalities. C282Y heterozygotes selected from family studies do not have greater serum iron tests than wild type homozygotes, except for compound heterozygotes, and therefore should not require special followup. The discovery of abnormal iron tests in a C282Y heterozygote should lead to workup for other causes of iron overload.
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PMID:HFE based re-evaluation of heterozygous hemochromatosis. 1469 25

The current treatment of hereditary hemochromatosis (HH) consists of performing periodic manual whole blood phlebotomies. Erythroapheresis (EPH) is considered to be an alternative procedure if the classic treatment is contra-indicated. A prospective study of 13 consecutive cases of HH were included in a periodic EPH program with the aim of assessing the efficacy, feasibility, and tolerability of EPH in the treatment of HH by induction and maintenance. Iron depletion (ferritin <20 microg/l) was achieved in all patients after a mean of 6.7 +/- 2.9 months of treatment and a mean of 13.5 +/- 7.2 EPH sessions. The procedure was well tolerated and there were no complications. After a follow-up period of 10.5 +/- 6.6 months, only four patients have required further maintenance sessions beyond 6 months after completing the induction therapy. The efficacy, speed, tolerability, and more favorable schedule of an EPH program facilitate treatment of HH.
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PMID:In hereditary hemochromatosis, red cell apheresis removes excess iron twice as fast as manual whole blood phlebotomy. 1221 Jul 12

Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as a biologic catalyst. However, when not appropriately shielded or when present in excess, iron plays a key role in the formation of extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. These systems normally tightly control iron homeostasis but their failure can lead to iron deficiency or iron overload and their clinical consequences. This review describes several rare iron loading conditions caused by genetic defects in some of the proteins involved in iron metabolism. A dramatic decrease in the synthesis of the plasma iron transport protein, transferrin, leads to a massive accumulation of iron in nonhematopoietic tissues but virtually no iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding transferrin receptor 2 lead to iron overload (hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary hemochromatosis (hemochromatosis type 1). Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause iron overload. Mutations in the gene encoding the iron exporter, ferroportin 1, cause iron overload characterized by iron accumulation in macrophages yet normal plasma iron levels. Plasma iron, together with dominant inheritance, discriminates iron overload due to ferroportin mutations (hemochromatosis type 4) from hemochromatosis type 1. Heme oxygenase 1 is essential for the catabolism of heme and in the recycling of hemoglobin iron in macrophages. Homozygous heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme iron in macrophages, hepatocytes, and many other cells and is associated with low plasma iron levels, anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron (or iron-sulfur cluster) export and the neurologic and cardiac manifestations of Friedreich ataxia are due to iron-mediated mitochondrial toxicity. Finally, patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus.
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PMID:Rare causes of hereditary iron overload. 1238

Gastrointestinal side effects were selected as the critical adverse effects on which to base the UL for iron. Although gastrointestinal distress is not a serious side effect when compared with the possible risk for vascular disease and cancer, the other side effects considered (impaired zinc absorption, increased risk for vascular disease and cancer, and systemic iron overload) did not permit the determination of a UL. Gastrointestinal distress is primarily observed in individuals who have consumed high levels of supplemental iron on an empty stomach. Large doses of iron supplements may inhibit zinc absorption when both are consumed in the fasting state, but zinc absorption is not impaired when supplementary iron is taken with meals. The relationship between iron intake and both vascular disease and cancer is unclear at the present time. With the possible exception of individuals living in Southern Africa who suffer from sub-Saharan iron overload, iron overload has not been shown to result solely from a high dietary iron intake. Moreover, no differences were found in the serum ferritin concentrations between individuals who fell in the lower and upper quartiles for total dietary iron intake in the Third National Health and Nutrition Examination Survey (NHANES 111) (Appendix Table H-5). Heterozygous carriers of the C282Y mutation most commonly associated with hereditary hemochromatosis could be at increased risk for accumulating harmful amounts of iron, but there are no direct observations to confirm this suspicion. Homozygotes and individuals with other iron-loading disorders may not be protected by the UL and are addressed under "Special Considerations".
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PMID:Iron: tolerable upper intake levels. 1245 26

HFE is a nonclassical class I molecule that associates with beta 2-microglobulin (beta 2m) and with the transferrin receptor. HFE accumulates in transferrin-containing endosomes, and its overexpression in human cell lines correlates with decreased transferrin receptor (TFR)-mediated iron uptake and decreased intracellular iron pools. A mutation that interferes with proper folding and assembly of HFE complexes results in a severe iron-overload disease hereditary hemochromatosis. We previously suggested that viruses could also interfere with iron metabolism through the production of proteins that inactivate HFE, similarly to classical class I proteins. In particular, we demonstrated in a transient expression system that human cytomegalovirus (HCMV) US2 targeted HFE for proteasomal degradation. Here we demonstrate that the stable expression of HCMV US2 in HEK 293 cells constitutively expressing HFE leads to loss of HFE expression both intracellularly and on the cell surface, and the significant reduction of classical class I expression. Both HFE and classical class I molecules are targeted to degradation via a similar pathway. This HCMV US2-mediated degradation of HFE leads to increased intracellular iron pools as indicated by reduced synthesis of TfR and increased ferritin synthesis. Whether this interference with regulation of iron metabolism potentiates viral replication and/or promotes damage of HCMV-infected tissues remains to be determined. Nevertheless, the deleterious effect of US2 on the expression of HFE and classical class I major histo-compatibility complexes (MHC) provides HCMV with an efficient tool for altering cellular metabolic functions, as well as supporting the escape of virus-infected cells from cytotoxic T lymphocyte (CTL)-mediated immune responses.
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PMID:A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules. 1245 2

Two HFE gene mutations, C282Y and H63D, underlie the vast majority of cases of hereditary hemochromatosis. We performed a cross-sectional primary care-based study to determine the allele frequency of the C282Y and H63D mutations and the penetrance of each of the affected genotypes defined by their presence. Patients had previously undergone transferrin saturation (TS) testing. A total of 4865 unselected frozen serum samples were analyzed to determine serum ferritin (SF) levels. Genomic DNA isolated from these samples was analyzed for the C282Y and H63D HFE mutations. Homozygotes for each mutation and compound heterozygotes were evaluated to determine clinical penetrance. The allele frequency of C282Y was 0.0507 among Caucasian and 0.0067 among African Americans; that of H63D was 0.1512 and 0.0263, respectively. TS was > or =55% in 83% of individuals with C282Y/C282Y, 14.5% of C282Y/H63D, and 5% of H63D/H63D; SF was > or =300 microG/L in 42, 9, and 5% of these genotypes, respectively. None of the 12 C282Y homozygotes had cardiac dysfunction or hepatic cirrhosis. Only 9/129 (7%) individuals with the genotypes C282Y/H63D or H63D/H63D had a SF > or =300 microG/L; many had explanations other than iron overload that accounted for this increase. Thus, the prevalence of the common HFE mutations is the same in our population as previously described. TS screening would detect most C282Y homozygotes but not the other two genotypes. The penetrance of C282Y/C282Y is significant. The biochemical penetrance of H63D/H63D and C282Y/H63D is modest and the clinical penetrance is low.
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PMID:Prevalence and penetrance of HFE mutations in 4865 unselected primary care patients. 1248 2

Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13.0% (0%) C282Y homozygotes, 5.8% (2.6%) H63D/C282Y compound heterozygotes and 1.9% (3.1%) S65C heterozygotes. The values for 420 Danish blood donors are shown in parentheses. The distribution of genotypes in group B was similar to that of the blood donors. Serum ferritin, transferrin iron saturation and pathological data were collected from 38 randomly selected C282Y homozygotes, 36 H63D/C282Y compound heterozygotes, 19 H63D heterozygotes, 17 S65C heterozygotes and 144 wild-types. All of the C282Y homozygotes and 28% of the compound heterozygotes were diagnosed as HH patients. There was no evidence of HH in the H63D homozygotes or S65C heterozygotes. Moreover, 7 wild-type patients, 2 C282Y heterozygote patients and one H63D heterozygote patient fulfilled the criteria for HH. The significant enrichment of HH among associated genotype samples submitted for HFE testing indicates that the clinical selection is generally adequate. However, the study showed substantial deviation in the selection efficiency among the various hospitals and general practitioners.
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PMID:HFE mutations and hemochromatosis in Danish patients admitted for HFE genotyping. 1251 43

In the HFE-gene era, precise diagnostic parameters remain important to characterize individual iron stores, because the indication for therapy and prognosis are mainly related to the extent of iron loading. The frequently used serum ferritin interferes with non-iron related factors such as inflammation and may produce falsely positive values. We used a SQUID-biosusceptometer in a large series of patients (n = 679) to measure liver iron concentration in the differential diagnosis and therapy control of hereditary hemochromatosis (SQUID = superconducting quantum interference device). This truly non-invasive technique is sensitive, reliable, fast (online results), and also cost-effective when compared to invasive liver biopsy. Recently, ferritin iron content was propagated as a better parameter than ferritin protein. However, we found a poor correlation between ferritin iron and individual liver iron concentrations in patients with iron overload. Ferritin iron saturation varied in a range between 3 and 10%, independent from liver iron concentration. No differences were found between patients with hemochromatosis and secondary iron overload disease. Only patients with liver cell damage had increased ferritin iron saturations. In conclusion the diagnostic values of serum ferritin protein and iron to assess iron overload are limited.
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PMID:Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary hemochromatosis. 1254 35

Rheumatoid arthritis is an inflammatory joint and systemic disease believed to be of autoimmune origin. Predisposing factors also include genetic factors, such as the presence of alleles HLA-DRB1 *04, (HLA-DRB1 *0401, *0404, *0405 and *0408) and, in other ethnic groups, of subtypes DRB1 *0101, *0102 and DRB1 *1001. These genetic factors are believed to raise the risk of developing the disease. In rheumatoid arthritis, as in other chronic inflammatory diseases, iron metabolism dysfunction has been observed and attributed to inflammation. In hereditary hemochromatosis, tissue sideropexia is associated with a peculiar form of arthropathy. C282Y is a point mutation involving the replacement of a cysteine with a tyrosine at position 282 of the HFE protein. When found in homozygosis, there is a close association with hereditary hemochromatosis, accounting for one of the causes of iron metabolism dysfunction observed in this disease. The aim of this study was to compare the frequency of C282Y in patients with rheumatoid arthritis with that in patients with different forms of spondylarthritis and to correlate these findings with iron metabolism parameters. In the group of patients with rheumatoid arthritis, 2/24 (8.34%) were found to be positive for the C282Y mutation in the case of heterozygosis compared with 3/24 (12.5%) of patients with spondylarthritis. In patients with the C282Y mutation, ferritin levels were significantly higher than those in controls; conversely, serum iron levels were higher in patients with spondylarthritis. Serum transferrin levels, although slightly higher in rheumatoid arthritis patients, showed no statistically significant differences.
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PMID:Prevalence of C282Y mutation in patients with rheumatoid arthritis and spondylarthritis. 1263 63

Experimental data suggest the antimicrobial peptide hepcidin as a central regulator in iron homeostasis. In this study, we characterized the expression of human hepcidin in experimental and clinical iron overload conditions, including hereditary hemochromatosis. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we determined expression of hepcidin and the most relevant iron-related genes in liver biopsies from patients with hemochromatosis and iron-stain-negative control subjects. Regulation of hepcidin mRNA expression in response to transferrin-bound iron, non-transferrin-bound iron, and deferoxamine was analyzed in HepG2 cells. Hepcidin expression correlated significantly with serum ferritin levels in controls, whereas no significant up-regulation was observed in patients with hemochromatosis despite iron-overload conditions and high serum ferritin levels. However, patients with hemochromatosis showed an inverse correlation between hepcidin transcript levels and the serum transferrin saturation. Moreover, we found a significant correlation between hepatic transcript levels of hepcidin and transferrin receptor-2 irrespective of the iron status. In vitro data indicated that hepcidin expression is down-regulated in response to non-transferrin-bound iron. In conclusion, the presented data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis. Although the causality is not yet clear, this interaction might result from a down-regulation of hepcidin expression in response to significant levels of non-transferrin-bound iron.
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PMID:Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. 1263 25


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