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)

Hereditary hemochromatosis (hh, type 1 hemochromatosis) is an autosomal recessive trait characterized by hyperabsorption of dietary iron. The disease trait occurs in approximately five per thousand Caucasians of northern European descent. The causative gene, designated HFE, was isolated and characterized in 1996; most individuals with hh are homozygous for a mutation resulting in a change from cysteine to tyrosine at residue 282 of the HFE protein (C282Y). Wild-type HFE protein binds to the transferrin receptor, and by an undefined mechanism the enterocyte is "programmed" to absorb an amount of dietary iron precisely matched to the body's needs. The C282Y mutant protein is not expressed on the cell surface and does not bind to the transferrin receptor; the result is an enterocyte programmed to absorb slightly more iron than required. Most individuals with hh display a common laboratory phenotype, an elevated transferrin saturation. Iron stores in excess of normal eventually occur in most men and some women. The prevalence of organ damage due to iron overload, however, remains a controversial issue. Published estimates range from less than 1% to "nearly all." The main reason for this discrepancy has been ascertainment bias. Retrospective studies have been biased in favor of individuals with morbid complications of hh, whereas screening studies of groups such as blood donors generally include only healthy subjects. We focus here on a review of studies that have attempted to avoid ascertainment bias. If biopsy-proven hepatic fibrosis and/or cirrhosis is employed as the single criterion for disease-related morbidity, clinical penetrance of hh occurs in 4% to 25% of homozygotes. This range, although narrower than in biased studies, is still wide and requires clarification. A large-scale population-based study has been sponsored by the National Institutes of Health to address this issue. Until results become available, the pragmatic approach is to continue to screen for hemochromatosis in the primary care setting and to maintain serum ferritin values at approximately 100 micro g/L or lower with phlebotomy therapy.
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PMID:Hereditary hemochromatosis. 1238 98

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

We report a method for detection of recurring side-chain patterns (DRESPAT) using an unbiased and automated graph theoretic approach. We first list all structural patterns as sub-graphs where the protein is represented as a graph. The patterns from proteins are compared pair-wise to detect patterns common to a protein pair based on content and geometry criteria. The recurring pattern is then detected using an automated search algorithm from the all-against-all pair-wise comparison data of proteins. Intra-protein pattern comparison data are used to enable detection of patterns recurring within a protein. A method has been proposed for empirical calculation of statistical significance of recurring pattern. The method was tested on 17 protein sets of varying size, composed of non-redundant representatives from SCOP superfamilies. Recurring patterns in serine proteases, cysteine proteases, lipases, cupredoxin, ferredoxin, ferritin, cytochrome c, aspartoyl proteases, peroxidases, phospholipase A2, endonuclease, SH3 domain, EF-hand and lectins show additional residues conserved in the vicinity of the known functional sites. On the basis of the recurring patterns in ferritin, EF-hand and lectins, we could separate proteins or domains that are structurally similar yet different in metal ion-binding characteristics. In addition, novel recurring patterns were observed in glutathione-S-transferase, phospholipase A2 and ferredoxin with potential structural/functional roles. The results are discussed in relation to the known functional sites in each family. Between 2000 and 50,000 patterns were enumerated from each protein with between ten and 500 patterns detected as common to an evolutionarily related protein pair. Our results show that unbiased extraction of functional site pattern is not feasible from an evolutionarily related protein pair but is feasible from protein sets comprising five or more proteins. The DRESPAT method does not require a user-defined pattern, size or location of the pattern and therefore, has the potential to uncover new functional sites in protein families.
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PMID:Functional sites in protein families uncovered via an objective and automated graph theoretic approach. 1258 52

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

Iron regulatory protein 2 (IRP2) is a mammalian cytosolic iron-sensing protein that regulates expression of iron metabolism proteins, including ferritin and transferrin receptor 1. IRP2 is ubiquitinated and degraded by the proteasome in iron-replete cells but is relatively stable in iron-depleted cells. Recent work has shown that IRP2 contains a unique 73-amino-acid domain that binds iron in vitro and undergoes iron-dependent oxidation and cleavage (J. Biol. Chem. 278 (2003), 14857). Several cysteines in the 73-amino-acid domain function as an in vitro iron-binding site. To assess the role of these cysteines in cellular iron- dependent degradation of IRP2, we mutagenized these cysteines in various combinations in the context of full-length protein and generated cell lines in which recombinant IRP2 expression was inducible. Iron-dependent degradation of IRP2 mutagenized at any or all of the cysteines of the putative degradation domain in cells was comparable to wild-type (WT). Both WT and cysteine mutant protein were stabilized in 3% oxygen. Treatment with sodium nitroprusside (SNP), an NO+ donor, caused a decrease in cellular IRP2 concentrations, but the SNP effect was abrogated by simultaneous addition of the iron chelator desferal and was not affected by cysteine mutations. Inhibition of endogenous heme synthesis with succinylacetone significantly inhibited iron- dependent degradation of IRP2. Addition of cobalt chloride inhibited degradation of both WT and mutagenized IRP2. Thus, we could not discern a role for the recently defined in vitro cysteine-dependent iron-binding site of IRP2 in cellular physiology. The early molecular events in iron-dependent degradation of IRP2 remain to be elucidated.
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PMID:The role of endogenous heme synthesis and degradation domain cysteines in cellular iron-dependent degradation of IRP2. 1297 33

We searched for metastasis-related genes in adenoid cystic carcinoma by suppression subtractive hybridization analysis of high and low metastasis cell lines. Twelve genes (ten previously identified and two novel sequences) were identified as being expressed at lower levels in high metastasis cell line Acc-M when compared to low metastasis cell line Acc-2. The known sequences corresponded to the genes for cysteine-rich angiogenesis induction factor (cyr61), chromosome 7 RP11-52501 clone, G-protein, WAS familial ferritin I heavy chain, jumping translocation breakpoint, eukaryotic translation elongation, folate receptor and three ribosomal proteins. Among them, the G protein and ferritin I heavy chain genes contained mutations in the high metastasis cell line. The two novel gene sequences have been named ACC metastasis-associated RNH and ACC metastasis-associated suspected protein (GenBank # AF522024 and AF522025, respectively). Taken together, these results suggest that reduced expression and/or mutation of several genes in the tumor cell line Acc-M are associated with high tumor metastasis, providing important molecular biological materials for further study of metastasis control and possible targets for cancer gene therapy.
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PMID:Study of the difference of high and low metastasis cell line's gene expression map and metastasis-related genes of adenoid cystic carcinoma. 1450 62

Iron is essential for oxidation-reduction catalysis and bioenergetics; however, unless appropriately shielded, this metal plays a crucial role in the formation of toxic oxygen radicals that can attack all biological molecules. Organisms are equipped with specific proteins designed for iron acquisition, export and transport, and storage, as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. This review describes several hereditary iron-overloading conditions that are confined to the brain. 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's ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron-sulfur cluster formation, and the neurologic and cardiac manifestations of Friedreich's ataxia are due to iron-mediated mitochondrial toxicity. 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. Finally, aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by loss-of-function mutations in ceruloplasmin gene that leads to misregulation of both systemic and central nervous system iron trafficking. Affected individuals suffer from extrapyramidal signs, cerebellar ataxia, progressive neurodegeneration of retina, and diabetes mellitus. Excessive iron depositions are found in the brain, liver, pancreas, and other parenchymal cells, but plasma iron concentrations are decreased. These conditions are not common, but awareness about them is important for differential diagnosis of various neurodegenerative disorders.
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PMID:Hereditary causes of disturbed iron homeostasis in the central nervous system. 1510 72

Iron overload causes impaired function of tissues and organs due to the increased iron storage in them. Hereditary hemochromatosis is the most frequent hereditary metabolic disorder, with lethal outcome without treatment. The genetic disorder is a mutation on the short arm of the 6. chromosome, which resulted a cysteine-tyrosine substitution on the 282. amino acid position (C282Y). This mutation is less frequent in the non-Caucasian population, in opposition to the other reported mutation (H63D). The risk of the development of the disease is the highest in people who are C282Y homozygotes or C282Y/H63D compound heterozygotes. The prevalence of hemochromatosis is 1.5-5.9 per thousand. Liver disease/cirrhosis, diabetes mellitus and hyperpigmentation are the classic signs of the disease. Primer hepatocellular cancer occurs in 30% of patients with liver cirrhosis, that it is the most common cause of death among them. The diagnosis is based on the detection of iron overload (transferrin saturation, serum ferritin level, iron concentration of the liver tissue) and on the genetic examinations. Early diagnosis makes the causal therapy possible, which is the removal of the iron excess by phlebotomy. Furthermore, the early detection of iron overload allows of prevention of the development of the disease. Based in these facts population screening seems to be necessary and cost-effective, but further studies are required to determine the exact screening strategy.
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PMID:[Iron storage disease]. 1555 8

To study the mechanism of toxicity of paraquat and formaldehyde, the response of oxidant-exposed cultured NIH3T3 cells to antioxidants or an iron chelator was investigated. Paraquat-induced cell death was reduced by treatment with 10 microM pyrrolidine dithiocarbamate (PDTC) and 10 microM desferrioxamine (DFO), but not with N-acetyl-L-cysteine (NAC). Cells were protected from formaldehyde-induced cytotoxicity by 1 mM NAC, but not by PDTC or DFO. Moreover, paraquat modulated the cellular iron regulatory system. Paraquat induced a time-dependent increase in the binding of iron regulatory protein 1 (IRP1) to iron-responsive element (IRE), and the enhanced IRP1 activity continued over 24 h. On the other hand, no induction of increased IRP1 binding to IRE was observed in rodent cells exposed to formaldehyde. Previously, we observed stimulation of EpRE-mediated ferritin mRNA expression in the cells exposed to hydrogen peroxide. However, paraquat did not induce any transcriptional activation of ferritin genes. These results suggest that intracellular iron may be involved in paraquat-mediated cytotoxicity and the influence of paraquat on iron metabolism differs from that of hydrogen peroxide.
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PMID:Different cytoprotective effect of antioxidants and change in the iron regulatory system in rodent cells exposed to paraquat or formaldehyde. 1566 34

A new metal-chelate adsorbent utilizing N-methacryloyl-(L)-cysteine methyl ester (MAC) was prepared as a metal-chelating ligand. MAC was synthesized by using methacryloyl chloride and L-cysteine methyl ester dihydrochloride. Spherical beads with an average diameter of 150-200 microm were produced by suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) and MAC carried out in an aqueous dispersion medium. Then, Fe(3+) ions were chelated directly on the beads. Properties such as specific surface area, specific pore volume and ligand occupation were determined. The specific surface area of the beads was found to be 18.9 m2/g. The total pore volume was 2.8 ml/g and represented a porosity over 52%. The average pore size of the poly(HEMA-MAC) beads was 620 nm. Fe(3+)-chelated beads were used in the adsorption of ferritin from aqueous solutions. Ferritin adsorption increased with increasing ferritin concentration. The maximum ferritin adsorption capacity of the Fe(3+)-chelated poly(HEMA-MAC) beads (Fe(3+) loading 0.81 mmol/g) was found to be 3.7 mg/g at pH 4.0 in acetate buffer. The non-specific ferritin adsorption on the poly(HEMA-MAC) beads were 0.4 mg/g. Adsorption behavior of ferritin could be modelled using both the Langmuir and Freundlich isotherms. Adsorption capacity decreased with increasing ionic strength of the binding buffer. Ferritin molecules could be adsorbed and desorbed five times with these adsorbents without noticeable loss in their ferritin adsorption capacity.
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PMID:Immobilized metal affinity beads for ferritin adsorption. 1600 24


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