Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The mechanism by which a novel major histocompatibility complex class I protein, HFE, regulates iron uptake into the body is not known. HFE is the product of the gene that is mutated in >80% of hereditary hemochromatosis patients. It was recently found to coprecipitate with the transferrin receptor (Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 1472-1477; Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X. Y., Tomatsu, S., Fleming, R.E. , and Sly, W. S. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 13198-13202) and to decrease the affinity of transferrin for the transferrin receptor (Feder et al.). In this study, HeLa cells were transfected with HFE under the control of the tetracycline-repressible promoter. We demonstrate that HFE and the transferrin receptor are capable of associating with each other within 30 min of their synthesis with pulse-chase experiments. HFE and the transferrin receptor co-immunoprecipitate throughout the biosynthetic pathway. Excess HFE is rapidly degraded, whereas the HFE-transferrin receptor complex is stable. Immunofluorescence experiments indicate that they also endocytose into transferrin-positive compartments. Combined, these results suggest a role for the transferrin receptor in HFE trafficking. Cells expressing HFE have modestly increased levels of transferrin receptor and drastically reduced levels of ferritin. These results implicate HFE further in the modulation of iron levels in the cell.
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PMID:Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation. 970 50

This study investigated the release of erythrocyte-derived iron from purified human monocytes obtained from healthy volunteers and hereditary hemochromatosis (HH) patients. After erythrophagocytosis of 59Fe-labeled erythrocytes, a complete transfer of iron from hemoglobin (Hb) to ferritin was observed within 24 hours in both control and HH monocytes. The iron was released from the monocytes in the form of ferritin, Hb, and as nonprotein bound low molecular weight iron (LMW-Fe). During the initial rapid phase (<1.5 hours), iron release mostly consisted of Hb and LMW-Fe, while in the later phase (>1.5 hours), it was composed of ferritin and LMW-Fe. The kinetics of iron release were identical for HH monocytes. A high percentage of the total amount of iron was released as Hb both by viable normal and HH monocytes, suggesting that iron release as Hb is a physiologic process, which may occur whenever the erythrocyte-processing capacity of macrophages is exceeded. Most remarkably, HH monocytes released twice as much iron in a LMW form as control cells. Iron released in the form of LMW-Fe readily binds to plasma transferrin and may contribute to the high transferrin saturation and the occurrence of circulating nontransferrin-bound iron observed in HH patients.
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PMID:Iron release from human monocytes after erythrophagocytosis in vitro: an investigation in normal subjects and hereditary hemochromatosis patients. 974 92

Genetic (hereditary) hemochromatosis is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39. Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excess iron storage eventually produces pituitary, pancreatic, cardiac, and liver dysfunction and death may result from cardiac arrhythmias, congestive heart failure, and/or hepatic failure or cancer. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations. Patients at risk for genetic hemochromatosis should be screened, identified, and treated as early as age 20 to prevent or minimize the deadly complications of hemochromatosis. Population screening should include measurements of serum iron concentration, total iron binding capacity (TIBC), percent saturation of transferrin, and serum ferritin concentrations. Family members of hereditary hemochromatosis patients are at increased risk and should be tested. Screening, identification and early treatment (phlebotomies, sometimes in combination with the use of Desferal or other iron-chelating agents) may help prevent or reduce iron-related organ damage and premature deaths. Early diagnosis and treatment will reduce the population of aging individuals with severe, complicated hemochromatosis and dramatically reduce medical costs (billions of U.S. dollars per annum) associated with the management of this disease.
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PMID:Hereditary hemochromatosis. 978 32

HFE is the protein product of the gene mutated in the autosomal recessive disease hereditary hemochromatosis (Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R. J., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal, G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., Meyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prasss, C. E., Quintana, L., Starnes, S. M., Schatzman, R. C., Brunke, K. J., Drayna, D. T., Risch, N. J., Bacon, B. R., and Wolff, R. R. (1996) Nat. Genet. 13, 399-408). At the cell surface, HFE complexes with transferrin receptor (TfR), increasing the dissociation constant of transferrin (Tf) for its receptor 10-fold (Gross, C. N., Irrinki, A., Feder, J. N., and Enns, C. A. (1998) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N. , Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U S A 95, 1472-1477). HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross et al., 1998). Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, we show that the expression of HFE reduces 55Fe uptake from Tf by 33% but does not affect the endocytic or exocytic rates of TfR cycling. Therefore, HFE appears to reduce cellular acquisition of iron from Tf within endocytic compartments. HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered. These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in hereditary hemochromatotic individuals lacking functional HFE.
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PMID:The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. 1008 50

Reference values for two ferritin assays (Tina-quanta Ferritin, Enzymun, both Roche Diagnostics, Mannheim, Germany) were established (136 males and 139 females). To rule out inflammation as well as iron deficiency in the reference population, subjects with the C-reactive protein concentration < 5 mg/l, and zinc protoporphyrin < 40 micromol/mol heme and the soluble transferrin receptor < 3 mg/l were selected. Taking into account latent iron deficiency as well as hereditary hemochromatosis the 5-95 percentile range was as follows: male, 27-365 microg/l; female, 13-148 microg/l for Tina-quanta and 12-151 microg/l for Enzymun. The Tina-quanta Ferritin assay showed a very good correlation (r > or = 0.990) to Enzymun ferritin, Ferritin Abbott (Abbott Diagnostics, Delkenheim, Germany), N Latex Ferritin (Dade Behring, Marburg, Germany) and the Ferritin Chiron (Chiron Diagnostics, Fernwald, Germany). However, the slopes of the standard principal component method analysis were calculated to be between 1.03 (Enzymun) and 1.41 (N Latex Ferritin). For four assays the median recovery of the 3rd International Recombinant Ferritin Standard (NIBSC 94/572) measured by serial dilution was 89-109%. The N Latex Ferritin assay recovered half of the target values. Because of the good correlation with other assays, a matrix effect is likely. The question arises whether the manufacturers' agreement on the recombinant ferritin standard would harmonize ferritin measurement.
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PMID:Reference values for a homogeneous Ferritin assay and traceability to the 3rd International Recombinant Standard for Ferritin (NIBSC code 94/572). 1053 31

Hereditary hemochromatosis (HHC) is one of the most common inherited disorders in the Caucasian population. Diagnosis usually made after an elevation in ferritin and serum transferrin saturation is noted, often accompanied by asymptomatic hepatomegaly. Diagnosis is confirmed by genetic testing or liver biopsy. Damage to organs is due to excessive intestinal iron, which is transported to and then deposited in the liver parenchyma, and the heart, skin, and endocrine organs, causing skin pigmentation, development of cirrhosis and hepatic carcinoma, diabetes and endocrine failure, and heart failure. Bony changes can be manifested by arthritis, often in non-weight-bearing joints. The treatment of HHC is phlebotomy, which depletes iron stores. When diagnosis is made before organ damage occurs, treatment can prevent manifestations of the disease. Skin pigmentation and some cardiac damage may reverse on depletion of iron stores, but liver and endocrine damage is rarely reversible. Arthropathy is also not reversible, and often continues to progress even with effective treatment. When hemochromatosis is diagnosed, all first degree relatives of the patient should undergo genetic testing. With early detection and treatment this can be a manageable chronic disease. If undetected, it is potentially fatal.
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PMID:Hereditary hemochromatosis: diagnosis and treatment in primary care. 1054 25

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular "labile iron pool." The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.
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PMID:HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. 1057 8

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, resulting in an increased iron deposition and multiorgan failure. Recently a candidate gene of HH, termed HFE, has been identified on chromosome 6, coding for a protein homologous to major histocompatibility complex (MHC) class I molecules. Two mutations of the hemochromatosis gene leading to an exchange of cysteine to tyrosine at aminoacid 282 and histidine to asparagine at aminoacid 63, are retained responsible for the development of hereditary hemochromatosis. The Cys282Tyr-mutation disrupts a disulfid bond and thus abrogates binding of the mutant HFE-protein to beta 2-microglobulin and its presentation on the cell surface. The His63Asp-mutation seems to play a role in pH-regulated dissociation of the transferrin receptor/transferrin complex in the lysosome. Mutations of the HFE-protein alter the affinity of the transferrin receptor for its ligand transferrin and may thus cause an intracellular accumulation of iron. Knowledge of the responsible gene allows a molecular diagnosis of HH. The new genetic marker can be used for screening and confirmation of HH reducing the need for confirmatory liver biopsies. Compared to standard screening parameters like ferritin and transferrin saturation genetic testing will allow the diagnosis of HH in an early, asymptomatic state before iron accumulation has occurred. As a normal life expectancy of patients with HH can be achieved if iron reduction is initiated early, genetic testing may thus be of great benefit for patients with HH.
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PMID:[Hereditary hemochromatosis--new developments after discovery of the HFE gene]. 1066 43

In 1996 two mutations in Hfe, the gene affected in hereditary hemochromatosis, were identified as C282Y (c.845G. A) and H63D (c.187C. G). Immunohistochemical studies have localized the protein product of Hfe to the deep crypts of the duodenum, the maximum site of iron absorption. To date, there are no published data on the cellular location and regulation of Hfe in patients with hemochromatosis who are homozygous for C282Y. The aim of this study was to identify the cellular localization of Hfe in genotyped individuals and to study possible regulation of this protein by the mutations described in the Hfe gene locus and iron deficiency. Duodenal biopsy specimens and serum for iron, ferritin, and transferrin saturation were taken from controls (n = 10) and patients with hereditary hemochromatosis (n = 10) and iron deficiency anemia (n = 10). All participants were genotyped for C282Y and H63D mutations. Expression of Hfe in the duodenum was demonstrated by immunohistochemistry. Hfe was expressed in the deep crypts of the duodenum in all three groups in a perinuclear fashion. Hfe staining was weaker in the hemochromatosis and iron deficiency patients (mean transferrin saturation 69.6%, SD 23% and 15%, SD 11%, respectively) when compared to controls (mean transferrin saturation 33.1%, SD 15%). There was no difference in the intensity of Hfe staining within the hemochromatosis group who were iron overloaded when compared to their iron-depleted counterparts. In summary, Hfe is expressed strongly in the deep crypts of the small intestine of normal subjects. Homozygosity for C282Y and conditions of iron deficiency result in a downregulation of Hfe. Furthermore, Hfe is not regulated by therapeutic iron depletion in patients with hemochromatosis who are homozygous for the C282Y mutation.
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PMID:Immunohistochemistry of the Hfe protein in patients with hereditary hemochromatosis, iron deficiency anemia, and normal controls. 1077 70

We compared 48-hour urinary iron excretion after a twice-daily subcutaneous bolus injection of deferoxamine and after 12 hours of subcutaneous continuous infusion of the drug in 27 patients with iron overload (mean age, 55.7 years). In most patients, the iron overload was due to multiple transfusions administered during chemotherapy or as part of supportive care for a hematologic or oncologic disorder. One patient had sickle cell anemia and 1 had hereditary hemochromatosis and spherocytosis. Similar urinary iron excretion was observed with the 2 methods of administration; mean +/- SD values were 6935.3 +/- 3832.3 microg/48 hours with subcutaneous bolus injection and 6630.4 +/- 3606.9 microg/48 hours with subcutaneous continuous infusion (P =.3). Twenty-six patients (96.3%) chose to continue therapy with bolus injection. The long-term efficacy of bolus injection was evaluated by measuring the serum ferritin concentration at regular intervals for a follow-up time of 20.1 +/- 4.5 months. Ferritin concentration decreased to below 1000 microg/L in 73% of the patients and to below 500 microg/L in 42% and became normal in 26%. Best results were obtained in patients who were no longer receiving blood transfusions when chelation therapy was initiated. Three of 26 patients (11.5%) had mild, transient side effects after bolus injection. Larger prospective, randomized studies must be conducted before deferoxamine bolus injection can be routinely recommended for patients with iron overload. (Blood. 2000;95:2776-2779)
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PMID:Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. 1077 20


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