Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metallothionein biosynthesis is not induced by extracellular copper in Menkes Kinky hair disease (MKHD) or in normal cultured fibroblasts under the conditions of these experiments. In the presence of copper, MKHD fibroblasts also incorporated less cysteine than did normal fibroblasts. Extracellular cadmium greatly enhanced the uptake of cysteine in both normal and MKHD cultures. By the technique of polyacrylamide gel electrophoresis, it was demonstrated that metallothionein is induced by cadmium in normal and MKHD-cultured fibroblasts.
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PMID:Inducibility of metallothionein biosynthesis in cultured normal and Menkes kinky hair disease fibroblasts: effects of copper and cadmium. 47 76

Fibroblasts from infants with Menkes kinky hair syndrome, which accumulate excessive quantities of copper, are thought to represent a disorder of copper storage or transport. Because of this abnormality, it was thought that they might provide a useful system for investigation of the presumed storage or transport protein metallothionein. Data are presented which are consistent with defective copper efflux from the mutant cells. Because of the more specific role of metallothionein in cadmium detoxification, studies of cadmium metabolism were undertaken which demonstrated abnormal cadmium retention and metallothionein induction in the mutant cells. The association, therefore, of a defect of cadmium metabolism and storage with an abnormality of copper efflux provides evidence implicating metallothionein in copper transport for fibroblasts.
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PMID:Role of metallothioneins in copper transport in patients with Menkes syndrome. 68 47

Two species of metallothioneins were isolated from both normal and Menkes kinky hair disease (MKHD) patient livers. Atomic absorption determination of metals indicated that the patient liver metallothioneins had lower copper and cadmium content than normals. Isotope exchange studies, carried out by incubating native metallothioneins with copper-64 or cadmium-109 demonstrated a decreased affinity for copper and an increased affinity for cadmium in both MKHD metallothioneins. An hypothesis is proposed in which metallothionein functions as an intracellular copper carrier and is responsible for the transport of copper between the cells and the surrounding. Change in the copper affinity of the metallothioneins was suggested to be the major abnormality in MKHD.
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PMID:Metal-binding studies of metallothioneins in Menkes kinky hair disease. 69 18

The aim of this article is to emphasize the important role that copper plays in the function of nerve cells. We are reporting preliminary data which suggest that the swelling of axons which we produce in rats by iminodipropionitrile, IDPN, is due to its chelating action on copper, and how conversely supplementation with copper abolishes both symptoms and lesions. The copper values we obtained by atomic absorption spectrophotometry of the spinal cord and brain from the animals fully support this contention. In comparing these results with the diseases that are known to be due to copper deficiency, namely Menkes disease in man, swayback in lambs and several neurological mutant mice, we find not only similar axonal swellings, but also amelioration of symptoms and lesions by early administration of copper. Considering the main forms in which copper is present, we discuss the cuproproteins, i.e. ceruloplasmin and metallothionein, and their role in transport and delivery of copper to various organs. Further, the many cuproenzymes i.e. superoxide dismutase, tryptophan-2,3-dioxygenase, lysine oxidase, cytochrome oxidase, monoamine oxidases, tyrosinase, dopamine-beta-hydroxylase and d-amino levulinate dehydratase are noted for their roles in the nervous system. Finally, we suggest that neuronal copper deficiency should be more fully investigated as a possible etiological factor in the more common neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis, ALS.
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PMID:Deficiency of copper can cause neuronal degeneration. 161 61

The copper concentration was investigated in the cultured astrocytes from macular mice, an animal model of Menkes disease. An excessive amount of copper was accumulated in the astrocytes as copper-metallothionein. These results show that the underlying genetic defect of the macular mouse is expressed in the astrocytes. A similar situation may exist in Menkes disease and cause a failure of copper transport to neurones.
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PMID:Genetic expression of Menkes disease in cultured astrocytes of the macular mouse. 177 48

These studies were designed to determine if macular mutant mouse, which is a proposed animal model of Menkes' kinky-hair disease, is sensitive to the acute toxic effect of Cu as compared to normal and heterozygote mice. Single sc injection of Cu were administered to 6- to 8-day-old mice, and mortalities were recorded for 30 days. The copper treatment at high doses (12 to 25 mg Cu/kg) was very toxic to mutant mice as compared to normal mice, and almost all mutant mice died within 10 days after injection. The effect of Cu toxicity on heterozygote mice was intermediate. The LD50 values 3 days after injection of Cu were 29.5 mg Cu/kg for normal mice, 23.5 mg Cu/kg for heterozygote mice, and 15.5 mg Cu/kg for mutant mice. In Cu-injected mutant mice (11 and 18 mg Cu/kg), significant elevations in serum aspartate aminotransferase and lactate dehydrogenase activity occurred as compared to Cu-injected normal and heterozygote mice. However, no significant elevations in serum creatinine and urea nitrogen contents in Cu-injected mutant were observed as compared to normal and heterozygote mouse. No significant differences in hepatic metallothionein(MT) and MT-1 mRNA, and serum ceruloplasmin oxidase activity levels were observed between Cu-injected normal and mutant mouse. These results indicated that macular mutant mice was sensitive to the acute toxic or hepatotoxic effects of Cu as compared to normal and heterozygote mice.
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PMID:Copper-induced toxicity in macular mutant mouse: an animal model for Menkes' kinky-hair disease. 187 75

Menkes' disease is an inherited disturbance of copper metabolism. Addition of copper to the medium of cultured fibroblasts and lymphoblasts from patients with Menkes' disease results in an increased induction of metallothionein. We investigated the metallothionein induction in response to copper and zinc in muscle cells (myoblasts and myotubes). Metallothionein synthesis was analyzed by gel electrophoresis of labeled proteins and metallothionein synthesis in muscle cells was compared with the synthesis in fibroblasts. The induction by copper was higher both in muscle cells and in fibroblasts from the Menkes' patient compared to the control cells. Hybrid myotubes obtained by fusion of control myoblasts and Menkes' myoblasts render a system in which complementation can be studied. Metallothionein synthesis in hybrid myotubes occurred at a level intermediate between the synthesis in Menkes' and control myotubes. The abnormal accumulation of copper-induced metallothionein was only partially corrected by fusion with normal cells. Metallothionein induction by zinc was similar in Menkes' and control fibroblasts. Combination of copper and zinc yielded no differences in additional metallothionein synthesis for Menkes' cells and control fibroblasts. Therefore, metallothionein induction in Menkes' disease can primarily be accounted for by copper rather than by zinc.
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PMID:Metallothionein in Menkes' disease: induction in cultured muscle cells. 208 40

Fibroblasts from the brindled mouse model of Menkes disease are known to accumulate excess copper. Most of the copper in the cytosol of these fibroblasts is bound to metallothionein (MT), which is elevated in Menkes or brindled mouse fibroblasts. Copper accumulation by normal fibroblasts containing excess MT was examined to determine if the excess copper accumulation phenotype was secondary to excess MT or associated with the primary defect in fibroblasts from the brindled mice. MT was induced in normal fibroblasts by copper, zinc or dexamethasone to levels comparable with those in brindled mice fibroblasts, as determined by radioimmunoassays. Normal fibroblasts containing excess MT accumulate copper normally, i.e. they do not exhibit the excess copper accumulation phenotype. Consistent with this result, copper efflux from normal fibroblasts containing excess MT was also normal. The data suggest that one function of the protein associated with the primary defect is to help determine how much copper is taken up and retained by fibroblasts and other cell types exhibiting the excess copper phenotype in Menkes disease. The capacity of this protein is apparently exceeded in normal fibroblasts if serum or albumin is not present extracellularly to limit total copper uptake. Consistent with a defect in an intracellular protein, the kinetics of copper transport by brindled mice fibroblasts were found to be normal.
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PMID:The relationship of excess copper accumulation by fibroblasts from the brindled mouse model of Menkes disease to the primary defect. 233 1

The proteins that bind copper when it first enters cells are likely to play roles in its intracellular distribution and utilization. When hepatocytes were incubated with 64Cu(II), the time-dependence of the subcellular distribution of 64Cu was consistent with one or more cytosolic proteins distributing copper to the mitochondrial and nuclear fractions. Cytosolic copper was reproducibly distributed among four protein fractions from Sephadex G-150 columns at the earliest time (1 min) and at the lowest concentration used [2 microM-64Cu(II)] with both rat and mouse hepatocytes. Copper binding to proteins in these functions was sensitive to copper metabolic status. Hepatocytes from nutritionally copper-deficient rats or neonatal (9-30 days old) developing rats showed an inverse correlation between copper binding to metallothionein and copper binding to proteins in fraction I (approximately 88 kDa apparent) and fraction II (approximately 38 kDa apparent). The distribution of cytosolic 64Cu from the brindled-mouse model of Menkes disease indicated decreased binding by a protein in fraction I. Brindled-mouse hepatocytes also contain decreased levels of a approximately 55 kDa protein or subunit, which most likely represents a liver-specific secondary response to the primary defect. The results are consistent with one or more copper-binding proteins in fractions I and II having significant functions in intracellular copper metabolism.
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PMID:Cytosolic copper-binding proteins in rat and mouse hepatocytes incubated continuously with Cu(II). 236 78

Menkes' kinky hair disease, a lethal X-linked recessive trait, is characterized by abnormal copper accumulation in several non-hepatic tissues. The level of many copper enzymes is severely reduced, leading to damage of the connective and nervous tissues of the patients. Cultured skin fibroblasts from Menkes' patients retain more copper then normal controls, and the excess metal is bound to metallothionein. Low doses of copper in the media induce MT gene transcription in Menkes' but not in normal cells. Transfection experiments using a plasmid containing the mouse MT-I promoter fused to the enzyme chloramphenicol acetyl transferase show that the activation of the mMTI promoter is in trans. Two other effects are observed in Menkes' cells: (a) two heat-shock like proteins are synthesized in response to low doses of copper in the growth medium, and (b) Menkes' cells are more sensitive then normal fibroblasts to copper toxicity. Our interpretation of these results supports a model for a defect in one or more steps in copper metabolism or transport.
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PMID:Abnormal copper metabolism and regulation of metallothionein gene expression in Menkes' disease. 295 38


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