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)

A 17-year-old male patient appeared with the biochemical liver damage associated with hypoceruloplasminemia and mild iron overload. Genetic analysis identified a compound heterozygosity of ATP7B responsible for the primary copper toxicosis of Wilson disease without mutations in HFE. A liver specimen consisted of cirrhotic nodules of large-sized hepatocytes with fatty change and those of fat-free small-sized hepatocytes. Histochemically, iron was distributed diffusely in the small-sized hepatocytes, while copper grains appeared in a few of the hepatocytes near the fibrous bands. X-ray microanalysis on the liver tissue fixed with a 0.1% osmium tetroxide solution and embedded in epoxy resin disclosed (1) complex formation of copper with sulfur, and iron with phosphorus in the hepatocyte lipofuscin particles, (2) intraparticle localization of the cuprothionein in the less dense matrix and ferric proteins in the dense matrix, and (3) high affinity of the cuprothionein to lead staining. Considering the fact that ceruloplasmin is the major ferroxidase essential for iron efflux, iron deposits in the hypoceruloplasminemic patients with Wilson disease are not a complication, but a natural event. This study disclosed for the first time the diagnostic ultrastructures of Wilson disease, which might represent different detoxification processes to the reactive metals of copper and iron.
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PMID:Copper- and iron-rich matrices in hepatocellular lipofuscin particles of a young male patient: diagnostic ultrastructures for Wilson disease. 1718 32

Wilson disease is an inherited, autosomal recessive, copper accumulation and toxicity disorder that affects about 30 individuals per million. This rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase, which is important for copper excretion into bile, leading to copper accumulation in the liver. Toxic copper concentrations can also be found in the brain and kidney, and clinical phenotypes include hepatic, haemolytic, neurologic and psychiatric diseases. Diagnosis is based on the combination of clinical features and findings such as increased urinary copper excretion, reduced levels of serum ceruloplasmin, high concentrations of copper in liver tissues and Kayser-Fleischer rings. Genetic studies are also becoming available for clinical use, but the utility of direct mutation analysis is limited. Wilson disease can be treated, and early diagnosis is essential: the goal of therapy is to reduce copper accumulation either by enhancing its urinary excretion or by decreasing its intestinal absorption. Medical therapies include penicillamine, trientine, zinc and tetrathiomolibdate. Liver transplantation is a relatively successful treatment option when medical therapy fails or in case of acute liver failure, even though it is also characterized by short- and long-term complications.
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PMID:Wilson disease--a practical approach to diagnosis, treatment and follow-up. 1738 11

The clinical manifestations of Wilson disease (WD) are varied and challenging. We conducted the current study to present the phenotypic characteristics and follow-up for a large cohort of patients with WD. We reviewed the medical records of 282 cases of WD (male:female ratio, 196:86) for clinical features, investigations, treatment, and outcome data. The clinical presentations were as follows: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and "presymptomatic," 15 (5.3%). Mean age was 15.9 years. Presymptomatic patients and those with the hepatic form of WD were younger and patients with osseomuscular and psychiatric forms were older than neurologic patients. The mean duration of illness at the time of diagnosis was 28 months. Predominant neurologic features were as follows: parkinsonism, 62.3%; dystonia, 35.4%; cerebellar, 28%; pyramidal signs, 16%; chorea, 9%; athetosis, 2.2%; myoclonus, 3.4%; and behavioral abnormalities, 16%. Kayser-Fleischer (KF) rings were seen as follows: neurologic patients, 100%; hepatic patients, 86%; and presymptomatic patients, 59%. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24-hour urinary copper excretion was increased in 70% of patients. Neuroimaging (computed tomography/magnetic resonance imaging) and electrophysiologic abnormalities were seen in many patients. Overall, 195 patients were on D-penicillamine therapy and 182 on zinc sulphate. Follow-up data, available for 225 patients, for a mean duration of 46 months, revealed improvement in 176, no change in 20, and deterioration in 6. Twenty-three patients died. To conclude, despite increased awareness and recognition and significant inroads into therapeutic frontiers, follow-up remains poor in developing countries and a return to previous level of functioning is not universal.
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PMID:Wilson disease: description of 282 patients evaluated over 3 decades. 1743 91

The aims of this study were evaluate motor, somatosensory, visual and auditory brainstem evoked potential (MEP, SEP, VEP, ABER) changes in Wilson disease (WD) and correlate these with magnetic resonance imaging (MRI) and clinical findings. Neurologic WD diagnosed on the basis of clinical, ceruloplasmin and Kayser-Fleischer ring were evaluated including pedigree charting, hepatic, renal, hematologic and osteoarticular manifestations. Blood counts, serum chemistry, MRI, MEP to tibialis anterior, tibial SEP, VEP and ABER were performed. Evoked potential (EP) changes were correlated with clinical and MRI findings. Eighteen WD patients were recruited from 17 families whose mean age was 16 years. Movement disorders were present in 14, cognitive decline in 12 and pyramidal signs in 12 patients. MRI revealed involvement of basal ganglia in 80%, thalamus in 40%, brain stem in 46.7% and subcortical white matter in 53.3%. MEP was abnormal in 35.7%, SEP in 30.8%, VEP in 57% and ABER in 61.5% patients; the latter three EP changes were subclinical. Frequency and number of EP abnormalities were higher with increasing severity of illness. SEP, VEP and ABER reveals subclinical abnormality and MEP helps in documenting both clinical and subclinical abnormalities. Number of EP abnormalities increases with increasing clinical severity of WD.
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PMID:A study of clinical, MRI and multimodality evoked potentials in neurologic Wilson disease. 1743 7

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

Wilson disease (WND), an autosomal recessive disorder of copper transport, is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic cirrhosis and neuronal degeneration are the major symptoms of WND, and mutations in the ATP7B gene are associated with WND. We have identified 28 different mutations in the ATP7B gene, including six novel variations, in 120 unrelated Korean patients with WND. Molecular defects in ATP7B were present in only 75.0% of Korean WND patients, with the most common mutation, p.Arg778Leu, having an allele frequency of 39.2%. To evaluate the functional defects of ATP7B caused by novel mutations, we used a yeast complementation system, and we used confocal microscopy to localize each mutation after transient expression in mammalian cells. Six novel variations were cloned into a yeast expression vector and two into a mammalian expression vector for confocal analysis. We found that c.2785A>G (p.Ile929Val) and c.3316G>A (p.Val1106Ile) were rare polymorphisms, whereas the others were novel variations disturbing ATP7B function.
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PMID:Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. 1758 12

Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new mutations not previously reported were identified: European white (p.L217X, c.918_931, c.1073delG, c.3082_3085delAAGAinsCG, p.V536A, p.S657R, p.A971V, p.T974M, p.Q1004P, p.D1164N, p.E1173G, p.I1230V, p.M1359I, c.2355+4A>G), Sephardic Jewish (p.Q286X), Filipino (p.G1149A), Lebanese (p.R1228T), Japanese (p.D1267V) and Taiwanese (p.A1328T). All but one missense variant have strong evidence for classification as disease-causing mutations. In the patients reported here, we also identified 20 nucleotide substitutions, six not previously reported, which cause silent amino acid changes or intronic changes. Documentation and characterization of all variants is essential for accurate DNA diagnosis in WND because of the wide range of clinical and biochemical variability.
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PMID:New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. 1837 11

Wilson disease (WD) is a recessively inherited copper storage disorder mainly affecting liver and brain. Genotype/phenotype correlations have been report ed but as yet not regarding psychic symptoms. Our aim was to investigate if a correlation might exist between genotype and phenotype concerning psychopathology and/or personality traits in patients with treated WD. Nine homozygous and three compound heterozygous Swedish patients were retrospectively investigated, representing four different mutation settings. Psychopathological symptoms were studied using the Comprehensive Psychopathological Rating Scale (CPRS), personality traits using the Karolinska Scales of Personality (KSP) and mutations were analyzed by manifold sequencing. Psychopathological symptoms: Patients with the Trp779Stop mutation had the lowest scores on the total CPRS, due to less pronounced reported CPRS items, as compared to the other three groups of patients. Compound heterozygotes for the His1069Gln/Arg1319Stop mutation showed the highest total CPRS scores. Personality traits: Patients homozygous for the Trp779Stop and the Thr977Met mutations had high scores on Psychopathy related scales whereas patients with His1069Gln/Arg1319Stop mutations had the lowest scores on these scales. Serum ceruloplasmin levels were undetectable in all patients with the Trp779Stop and Thr977Met mutations. The results show a trend towards a genotype/phenotype correlation regarding psychopathological symptoms and personality traits in treated patients with WD. If replicable, these results might contribute to the elucidation of the possible clinical importance of functionally deleterious gene mutations in WD psychopathology and personality traits.
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PMID:Psychopathology and personality traits in patients with treated Wilson disease grouped according to gene mutations. 1852 2

Wilson disease is an inherited disorder of human copper metabolism, characterized by gradual accumulation of copper in tissues, predominantly liver and brain. The gene defect lies in the Wilson disease protein ATP7B, a copper transporting ATPase highly active in hepatocytes. In the liver, ATP7B is essential for excretion of excess copper into the bile and for copper loading of ceruloplasmin in the Golgi apparatus. The extrahepatic role of ATP7B is not yet completely understood. We analysed the intestinal expression of ATP7B in mice using RT-PCR, Western blot and indirect immunofluorescence. We found abundant expression of ATP7B in stomach and small intestine, but not in colon. Using confocal microscopy we demonstrate a Golgi localization of ATP7B in enterocytes. In response to elevated copper, the Wilson disease protein shows an intracellular trafficking pattern in the intestinal polarized cell line CaCo-2, moving away from the Golgi apparatus to dispersed vesicles. This suggests a role for intestinal ATP7B in sequestration of copper in intracellular vesicles for maintenance of copper homeostasis in the enterocyte. In conclusion, the expression of ATP7B in the small intestine might represent an additional regulatory mechanism to fine-tune intestinal copper absorption.
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PMID:Localization of the Wilson disease protein in murine intestine. 1867 1

Copper is a redox active metal that is essential for biological function. Copper is potentially toxic; thus, its homeostasis is carefully regulated through a system of protein transporters. Copper is taken up across the lumen surface of the small intestinal microvilli as cuprous ion by Ctr1. Cupric ion may also be taken up, but those processes are less well understood. Within the cell, intestinal as well as others, copper is escorted to specific compartments by metallochaperones. One, CCS, donates copper to superoxide dismutase. Another, COX17, delivers copper to additional chaperones within the mitochondria for synthesis of cytochrome c oxidase. A third chaperone, Atox1, delivers copper to the secretory pathway by docking with 2 P-type ATPases. One, ATP7A, is the protein nonfunctional in Menkes disease. This protein is required for cuproenzyme biosynthesis, and in the enterocyte it is required for copper efflux to portal blood. The second, ATP7B, predominantly expressed in liver, is required for copper metallation of ceruloplasmin and biliary copper excretion. Mutations in ATP7B lead to Wilson disease. Additional intracellular hepatic copper-binding proteins COMMD1 (copper metabolism MURR1 domain) and XIAP (X-linked inhibitor of apoptosis protein) may also be required for excretion. Other proteins involved in copper homeostasis may include metallothionein and amyloid precursor protein. Plasma protein transport of copper from the intestine to liver and in systemic circulation probably includes both albumin and alpha2-macroglobulin. Changes in the expression of copper "transporters" may be useful to monitor copper status of humans, provided a suitable cell type can be sampled.
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PMID:Role of copper transporters in copper homeostasis. 1877 2


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