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 dose response as well as kinetics of uptake and retention of copper and cadmium of normal and Menkes kinky hair disease (MKHD) cultured fibroblasts are described. In basal culture medium, intracellular copper concentration in MKHD fibroblasts was approximately 3 times that of control cultures. The intracellular copper concentration of MKHD cells was significantly higher than that of normal fibroblasts at medium copper concentrations below 20 microgram/ml. Death of MKHD cells occurred at medium copper concentrations between 15 and 20 microgram/ml with an intracellular copper level 3 times that at basal medium. Normal cells died at medium copper concentration above 30 microgram/ml with an intracellular copper concentration 19 times that at basal medium. These observations suggested the existence of a regulatory mechanism for maintenance and control of intracellular copper in normal fibroblasts which is effective at medium copper concentrations below 30 microgram/ml. This system is defective in MKHD fibroblasts. In basal medium MKHD and normal fibroblasts had similar intracellular cadmium concentrations; however, at higher medium cadmium concentrations MKHD cells had increased intracellular cadmium levels. The uptake of both 64Cu and 109Cd was significantly higher in MKHD cells than in normal cells, indicating that the uptake of 64Cu and 109Cd is not impaired in MKHD cells. A higher retention of 64Cu was observed in MKHD cells at both 37 degrees C and 4 degrees C. No obvious trend, however, was observed in the difference of retention of 109Cd between MKHD and normal cells. An impairment of egress of copper in MKHD cells is implicated by these results.
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PMID:Cell culture studies of Menkes kinky hair disease. 69 39

A study was carried out on the uptake of copper, zinc, or cadmium ions and their induction of metallothionein synthesis in Menkes' and normal lymphoblastoid cells. The main difference between Menkes' and normal cells in the uptake of these metal ions was an increased uptake of copper ions in Menkes' cells at a low concentration of CuCl2 (2.1 microM). The CuCl2 concentration necessary to induce metallothionein synthesis in Menkes' cells was 50 microM, whereas that in normal cells was about 200 microM. The levels of zinc or cadmium ions needed to induce metallothionein in Menkes' cells were similar to those in normal cells. At least four isomers of metallothionein were induced by copper, zinc, and cadmium ions in both types of cells. Metallothionein synthesis in Menkes' and normal cells was induced when the amounts of intracellular copper reached a threshold level of approximately 0.2 nmol/10(6) cells, and the rate of metallothionein synthesis in these cells was increased as a function of the amounts of intracellular copper (0.2-1.7 nmol/10(6) cells). These results indicate that the induction of metallothionein synthesis in lymphoblastoid cells is controlled by the level of intracellular copper, suggesting that the major defect in Menkes' cells is not due to the abnormal regulation of metallothionein synthesis but to an alteration of the copper metabolism in cells by which the levels of intracellular copper become larger than those in normal cells and just lower than the threshold level for induction of metallothionein synthesis.
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PMID:Induction of metallothionein synthesis in Menkes' and normal lymphoblastoid cells is controlled by the level of intracellular copper. 349 30

Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content. A mouse model is provided by hemizygotes for mutant alleles at the X-linked mottled locus. Herein we test the possibility that the primary defect in both species is in metallothionein gene regulation. We show that metallothionein-I messenger RNA (mRNA) (mouse) and metallothionein-II mRNA (human) are elevated in mutant fibroblasts. However, comparable dose-response curves in mutant and control cells are generated when mouse metallothionein-I mRNA concentrations are measured in cells exposed to varying concentrations of cadmium or copper (metallothionein inducers). Furthermore, when mutant and control cells are grown to achieve overlapping intracellular copper concentrations in the two cell types, metallothionein-I (mouse) and metallothionein-II (human) mRNA levels are proportional to the intracellular copper concentrations. Finally, in paired determinations in blotchy hemizygote and littermate kidneys containing comparable copper levels, metallothionein-I mRNA contents are very similar. The observations suggest that elevated intracellular copper in these mutants induces metallothionein synthesis by normal regulatory mechanisms.
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PMID:Metallothionein messenger RNA regulation in the mottled mouse and Menkes kinky hair syndrome. 357 89

Menkes' kinky-hair syndrome is an X-linked recessive neurodegenerative and connective-tissue disorder, with decreased serum copper and ceruloplasmin-copper oxidase concentrations and tissue-specific increases in copper content. Clinical manifestations can be related to relative copper deficiency and reduced activity of cuproenzymes in multiple organs. An animal model is provided by mice hemizygous for mutant alleles, such as the blotchy allele, at the X-linked mottled locus. This locus may be homologous in mouse and man. The basic defect is unknown but has been thought to reside in the regulation of the function or synthesis of metallothioneins. In the blotchy mouse and in cultured skin fibroblasts derived therefrom, we showed that the mutation specifically affects the metabolism of copper and not other trace metals. Excessive accumulation and abnormal (reduced) exit kinetics were demonstrated for copper but not for the related trace metals cadmium and zinc. While metallothionein-I messenger RNA (mRNA) concentrations were elevated in blotchy fibroblasts, the elevations in metallothionein-I mRNA in response to metallothionein inducers (cadmium, copper) were similar in blotchy and control cells. Further, metallothionein-I mRNA levels were indistinguishable in mutant and control fibroblasts containing equivalent intracellular copper concentrations. Finally, metallothionein-I mRNA content was not elevated in blotchy kidneys at early developmental stages, before storage of excessive copper. The aggregate data suggest that the basic defect in the blotchy mouse--and, by analogy, in Menkes' syndrome--does not reside in defective modulation of metallothionein function and does not cause abnormal regulation of metallothionein synthesis.
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PMID:Regulation of copper metabolism in the mottled mouse. 367 14

Cultured skin fibroblasts from patients with Menkes disease and Wilson disease were analyzed as to their sensitivities to copper and cadmium by means of a colony-forming ability and cell growth study. All the Menkes strains exhibited about 3-fold higher levels of resistance to cadmium, whereas the cytotoxicity of copper did not differ among the Menkes, Wilson and normal fibroblast strains. The resistance to cadmium of Menkes skin fibroblasts may provide a diagnostic marker of Menkes disease and useful or valuable model for the understanding of detoxification system against heavy metals.
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PMID:Increased cadmium resistance of skin fibroblasts from Menkes disease patients. 370 65

Cultured lymphoblasts derived from infants with Menkes' disease exhibit the same increased avidity for copper as do fibroblasts and most extrahepatic tissues from these patients. The Menkes' cells preferentially take up not only copper but also, on exposure to elevated metal concentrations, the other metallothionein-binding metals, zinc and cadmium. Menkes' lymphoblasts contain larger amounts of metallothionein than normal cells following exposure to each of these metals; the amount bound to this protein quantitatively accounted for the total cellular increment in metal in Menkes' cells. Induction of metallothionein synthesis caused both normal and Menkes' cells to subsequently take up increased amounts of 67Cu. These observations suggest that an enhanced capacity of Menkes' cells to accumulate metallothionein may be responsible for their increased uptake and retention of copper.
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PMID:Metallothionein accumulation may account for intracellular copper retention in Menkes' disease. 627 42

Metallothionein is a cysteine-rich, low molecular weight protein that binds zinc, copper and cadmium. It is inducible in liver, kidney and intestine by glucocorticoids, changes in the dietary zinc supply, acute administration of various metals, food restriction, infection, stress and endotoxin treatment. Regulation of synthesis involves altered gene expression. The protein is fairly rapidly degraded when zinc is the primary metal species bound, but the degradation rate is diminished when cadmium or copper are bound as well. The net result of metallothionein production seems to be accumulation of bound metal and/or intracellular metal redistribution. The accumulation of copper in various tissues of individuals with Menkes' and Wilson's diseases may be related to altered metallothionein turnover. The physiological function is not clear, but the response of metallothionein to hormonal stimuli is suggestive of an important role in cellular metabolism.
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PMID:Metallothionein--aspects related to copper and zinc metabolism. 641 69


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