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: EC:1.16.3.1 (ceruloplasmin)
5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The application of molecular genetics to haemochromatosis and experimental mutagenesis in animals has transformed our capacity to investigate the unique physiology of iron homeostasis-a key problem in biology and medicine. The identification of HFE, the principal determinant of adult haemochromatosis (HFE1; OMIM 235200) and TfR2, recently implicated in a rarer form of the inherited disorder (HFE3; OMIM 604250), and the promise of candidate genes for juvenile haemochromatosis (HFE2; OMIM 602390) and neonatal haemochromatosis (OMIM 231100) provide the foundation for important studies into the control mechanism of iron balance in humans. The rare conditions atransferrinaemia (OMIM 209300) and acaeruloplasminaemia (OMIM 604290), each associated with tissue iron overload, have already implicated the iron transport ligand transferrin and the copper transporter caeruloplasmin in the control of iron homeostasis. Gene mapping studies in animal mutants with anaemia due to defects in the uptake or tissue transfer of iron have yielded novel proteins involved in iron transport: DMT1 (brush border transporter of ferrous iron) in the mk/mk mouse, hephaestin (basolateral multi-copper ferroxidase) in the sex-linked anaemic mouse (sla) and ferroportin1 (basolateral iron exporter) in zebrafish weh mutants. The discovery of genes that determine heritable defects of iron absorption and regulation in animals and humans thus holds promise for a complete mechanistic understanding of the molecular pathophysiology of iron metabolism.
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PMID:Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. 1100 92

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.
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PMID:Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism. 1170 34

For many years it has been known that neoplastic cells express high levels of the transferrin receptor 1 (TfR1) and internalize iron (Fe) from transferrin (Tf) at a tremendous rate. Considering the high requirement of neoplastic cells for Fe, understanding its metabolism is vital in terms of devising potential new therapies. Apart from TfR1, a number of molecules have been identified that may have roles in Fe metabolism and cellular proliferation. These molecules include transferrin (Tf), the oestrogen-inducible transferrin receptor-like protein, transferrin receptor 2 (TfR2), melanotransferrin (MTf), ceruloplasmin, and ferritin. In the present review these latter molecules are discussed in terms of their potential functions in tumour cell Fe metabolism and proliferation. Further studies are essential to determine the specific roles of these proteins in the pathogenesis of cancer.
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PMID:The iron metabolism of neoplastic cells: alterations that facilitate proliferation? 1192 69

Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the ceruloplasmin (CP) gene, and is characterized by a unique combination of neurovisceral iron overload and iron deficiency anemia. We generated CP-deficient (CP(-/-)) mice to investigate the functional involvement of CP in iron metabolism. The mice showed a marked iron overload in the liver and mild iron deficiency anemia. We examined the expression of iron-metabolism genes in the duodenum and liver using TaqMan RT-PCR. The divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), and hephaestin (HEPH) genes were not up-regulated in the duodenum from CP(-/-) mice. These data suggest that the mechanism of hepatic iron overload in aceruloplasminemia is quite different from that in hemochromatoses and atransferrinemia. In the liver, CP(-/-) mice showed no increase of gene expression for DMT1 and transferrin receptors (TFR and TFR2), indicating that none of the known pathways of iron uptake is activated in hepatocytes of CP(-/-) mice. This result supports the hypothesis that CP mainly acts to release iron from cells in the liver.
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PMID:Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice. 1239 73

Hereditary hemochromatosis is characterized by marked variation of expression of the defect: very few homozygotes with the C282Y/C282Y HFE genotype have full-blown clinical disease, a larger number show biochemical stigmata of iron overload, and some seem normal biochemically. The following candidate genes have been examined in detail to determine whether polymorphisms in them may be responsible for this variation: transferrin, transferrin receptor 1, transferrin receptor 2, ferritin-L, ferritin-H, IRP1, IRP2, HFE, beta(2) microglobulin, mobilferrin/calreticulin, ceruloplasmin, ferroportin, NRAMP1, NRAMP2 (DMT1), haptoglobin, heme oxygenase-1, heme oxygenase-2, hepcidin, USF2, ZIRTL, duodenal cytochrome b ferric reductase (DCYTB), TNFalpha, keratin 8, and keratin 18. The coding sequence, exon-intron junctions, and promoters of each of these genes was sequenced in DNA from 20 subjects: 5 HFE C282Y/C282Y with clinical disease, 5 HFE C282Y/C282Y with normal/low ferritin levels and no disease, 5 wt/wt with high ferritin and transferrin saturation, and 5 wt/wt normal controls. When coding or promoter polymorphisms were encountered, DNA from large numbers of ethnically defined subjects was examined for these polymorphisms and a relationship between their existence and abnormalities of iron homeostasis was sought. Only in the case of one transferrin mutation did we find a strong relationship between the polymorphism and iron deficiency anemia. The putative genes that affect the expression of HFE mutations remain elusive.
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PMID:Seeking candidate mutations that affect iron homeostasis. 1254 38

Primary iron overload may be relatively common in African Americans, but its cause is incompletely understood. Thus, we evaluated genotype and phenotype characteristics of unselected African American index patients with primary iron overload who reside in central Alabama. All had hepatic iron concentration > or =30 micromol/g dry wt or > or =2.0 g of iron mobilized by phlebotomy to achieve iron depletion. Genotype analyses were performed in African American control subjects from the same region. There were 23 patients (19 men, 4 women); mean age at diagnosis was 52 +/- 12 years (1 SD) (range 32-69 years). Nine (39.1%) reported that they consumed > or =45 g of ethanol daily; five had chronic hepatitis C. Eight had some form of hemoglobinopathy or thalassemia. Mean serum transferrin saturation was 56 +/- 28% (range 15-100%). The geometric mean serum ferritin at diagnosis was 1076 ng/mL [95% confidence interval 297-3473 ng/mL]. Increased stainable liver iron was observed in hepatocytes only in 4 patients, in macrophages only in 8 patients, and in hepatocytes and macrophages in 8 patients. The mean quantity of iron mobilized by phlebotomy (corrected for iron absorbed during treatment) was 5.3 +/- 2.0 g (range 4.0-8.4 g). Iron removed by phlebotomy was greater in patients with hemoglobinopathy or thalassemia than in those without these forms of anemia (6.6 +/- 1.3 g vs 3.9 +/- 1.6 g, respectively; P = 0.0144). Daily consumption of > or =45 g of ethanol or chronic hepatitis C was not associated with an increased or decreased amount of phlebotomy-mobilized iron, on the average. The percentage of index patients positive for HFE C282Y was greater than that of controls (P = 0.0058). The respective percentages of phenotype positivity for HFE H63D, D6S105(8), and HLA-A*03 were similar in patients and controls. HFE S65C, I105T, and G93R were not detected in index or control subjects. Two of 13 patients were heterozygous for the ferroportin allele nt 744 G-->T (Q248H), although the phenotype frequency of this allele was similar in patients and 39 controls. Synonymous ferroportin alleles were also detected in some patients. The ceruloplasmin mutation nt 1099C-->T (exon 6; Arg367Cys) was detected in 1 of 2 patients tested. Abnormal alleles of beta-2 microglobulin, Nramp2, TFR2, hepcidin, or IRP2 alleles were not detected in either of the 2 patients so tested. We conclude that primary iron overload in African Americans is not the result of the mutation of a single gene. HFE C282Y, ferroportin 744 G-->T, and common forms of heritable anemia appear to account for increased iron absorption or retention in some patients.
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PMID:Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. 1463 44

The number of new genes implicated in iron metabolism has dramatically increased during the last few years. Alterations of these genes may cause hyperferritinemia associated or not with iron overload. Correct assignment of the specific disorder of iron metabolism requires the identification of the causative gene mutation. Here, we propose a rational strategy that allows targeting the gene(s) to be screened for a diagnostic purpose. This strategy relies on the age of onset of the disease, the type of clinical symptoms, the biochemical profile (elevated or normal serum transferrin saturation (TfSat)), the presence or not of visceral iron excess, and the mode of inheritance (autosomal recessive or dominant). Then, two main entities can be differentiated: genetic (adult or juvenile) hemochromatosis characterized by elevated TfSat, and hereditary hyperferritinemias where TfSat is normal (or only slightly modified). Adult genetic hemochromatosis (GH) is related mainly to mutations of the HFE gene, and exceptionally to mutations of the TFR2 gene. Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for hepcidin. Hereditary hyperferritinemias are linked to mutations of three genes: the L-ferritin gene responsible for the hereditary hyperferritinemia cataract syndrome (without iron overload), the ferroportin gene leading to a dominant form of iron overload, and the ceruloplasmin (CP) gene corresponding to an iron overload syndrome with neurological symptoms. The proposed strategic approach may change with the identification of other genes involved in iron metabolism.
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PMID:The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. 1584 97

In contrast to primary lysosomal diseases in young subjects, adult-onset liver storage disorders may be explained by non-lysosomal genetic defects. The aim of the present review is to summarize the genetic backgrounds of Japanese patients with hemochromatosis of unknown etiology, Wilson disease of primary copper toxicosis, and the black liver of Dubin-Johnson syndrome. Three patients with middle-age onset hemochromatosis were homozygous for mutations of HJV and two patients were homozygous for mutations of TFR2. Minor genes other than HJV and TFR2 might be involved in Japanese patients. Five of the six patients with Wilson disease were compound heterozygous, while the remaining patient was heterozygous for the mutation in ATP7B responsible for copper toxicosis. Involvement of MURR1 was not proved in the heterozygote of ATP7B. Because of ferroxidase deficiency,most patients had secondary lysosomes shared by cuprothioneins and iron complex. Six patients with Dubin-Johnson syndrome were homozygous or compound heterozygous for mutant MRP2. Despite complex metabolic disorders, the syndrome had a single genetic background. Thus, most patients with adult-onset lysosomal proliferation in the liver had genetic defects in non-lysosomal organelles, named the secondary lysosomal diseases. The proliferating lysosomes in these conditions seemed to be heterogeneous in their matrices.
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PMID:Genetic background of Japanese patients with adult-onset storage diseases in the liver. 1751 77

The cross-talk which has taken place in recent years between clinicians and scientists has resulted in a greater understanding of iron metabolism with the discovery of new iron-related genes including the hepcidin gene which plays a critical role in regulating systemic iron homeostasis. Consequently, the distinction between (a) genetic iron-overload disorders including haemochromatosis related to mutations in the HFE, hemojuvelin, transferrin receptor 2 and hepcidin genes and (b) non-haemochromatotic conditions related to mutations in the ferroportin, ceruloplasmin, transferrin and di-metal transporter 1 genes, and (c) acquired iron-overload syndromes has become easier. However, major challenges still remain which include our understanding of the regulation of hepcidin production, the identification of environmental and genetic modifiers of iron burden and organ damage in iron-overload syndromes, especially HFE haemochromatosis, indications regarding the new oral chelator, deferasirox, and the development of new therapeutic tools interacting with the regulation of iron metabolism.
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PMID:Iron and the liver: update 2008. 1830 82

Hepatocellular carcinoma (HCC) commonly develops in patients with underlying chronic liver disease. Additionally, the tumorous lesions of HCC patients are consistently characterized by the lack of iron accumulation even when arising in iron-loaded liver. However, the molecular mechanism leading to this observed phenomenon is currently poorly understood. In this study, all tumorous tissues from 24 HCC patients with chronic HBV infection were stained negative for iron when histologically assessed by Perls' Prussian blue stain, whereas excess iron deposits were present in 17 of the 24 adjacent non-tumorous liver tissues. To elucidate the concerted regulation of iron homeostasis in these patients, we studied the gene expression profiling of 42 relevant iron-regulatory genes in the tumorous and adjacent non-tumorous liver tissues of these HCC patients along with 10 normal liver controls. Expression for most of the iron-regulatory genes, including hepcidin, transferrin receptor 2 (TfR2), transferrin (Tf), ceruloplasmin (Cp) and iron regulatory protein 1 (IRP1), were significantly down-regulated in the tumorous tissues of these patients compared to the adjacent non-tumorous liver tissues and normal liver controls. On the other hand, expression of hepcidin, TfR2, ferroportin 1 and DMT1 were significantly up-regulated in iron-loaded non-cirrhotic non-tumorous liver tissues as compared with normal liver controls. Hence, the reduction of hepcidin expression within the iron-depleted tumorous lesions likely reflects the physiological consequence of the obligate demand for iron in the rapidly growing neoplastic cells, whereas the up-regulation of hepcidin expression in the iron-loaded adjacent non-tumorous liver tissues is likely a physiological response.
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PMID:Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences. 1930 63


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