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

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.
 ...
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.
 ...
PMID:Metallothionein messenger RNA regulation in the mottled mouse and Menkes kinky hair syndrome. 357 89

The characteristic feature of Menkes' disease is a maldistribution of bodily copper; decreased copper levels are present in the serum, brain, and liver, whereas excess levels are present in gut, kidney, and most other nonhepatic tissues. Using cultured fibroblasts, we have shown that low extracellular copper concentrations induce synthesis of metallothionein, a copper-binding protein, in Menkes' cells but not in normal cells. This is due to a defect in a diffusable regulatory factor that is probably involved in copper metabolism. To further understand the role of the defective factor in transcription, assays have been developed to study the metal-dependent binding of nuclear proteins to metallothionein gene control sequences.
 ...
PMID:Metallothionein gene regulation in Menkes' syndrome. 366 72

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.
 ...
PMID:Regulation of copper metabolism in the mottled mouse. 367 14

Menkes' disease, an inherited disorder of copper metabolism, is characterized by the accumulation of excess copper-metallothionein in certain tissues and cell types. Using cultured fibroblasts, we show that this is due to the ability of low concentrations of copper to induce metallothionein mRNA synthesis in Menkes' but not normal cells. We also show that copper, which is unusually toxic to Menkes' cells, induces the synthesis of 84 kd and 68 kd polypeptides tentatively identified as heat shock proteins. Transfection experiments with a cloned metallothionein fusion gene show that this is due to a defect in a diffusible factor involved in either metallothionein gene transcriptional regulation or copper metabolism.
 ...
PMID:Menkes' disease: abnormal metallothionein gene regulation in response to copper. 396 94

The pathogenesis of Menkes disease seems to be linked to metallothionein which binds to copper trapped within cells in some tissues. The only known therapy for this disease is parenteral administration of copper, but the effects are equivocal. We treated a patient with Menkes disease by giving vitamin C orally. The clinical manifestation and bone changes improved and the plasma copper and ceruloplasmin levels gradually increased. Vitamin C may prevent the binding of copper and metallothionein by its reducing effect, and excess copper would be released from the cells. Vitamin C treatment is a simple and physiological method, and should aid in clarifying the pathogenesis of the disease.
 ...
PMID:Menkes disease: is vitamin C treatment effective? 408 90

Cultured fibroblasts of 13 patients with the Menkes syndrome and two with a new subtype (type IX) of the Ehlers-Danlos syndrome (E-D IX patients) showed many very similar abnormalities in their copper and collagen metabolism. Both cell types had markedly increased copper concentrations and 64Cu incorporation, and this cation accumulated in metallothionein or a metallothionein-like protein, as previously established for Menkes cells. Histochemical staining indicated that copper was distributed diffusely throughout the cytoplasm in both cell types, this location being consistent with the accumulation in metallothionein. Both fibroblast types also had markedly low lysyl oxidase activity and distinctly increased extractability of newly synthesized collagen, whereas no abnormalities were present in cell viability, duplication rate, prolyl 4-hydroxylase activity, or collagen synthesis rate. A high negative correlation (P less than 0.001) was found in the pooled group of Menkes and E-D IX cells between cellular copper concentration (r = 0.804) or 64Cu incorporation (r = 0.863) and the logarithm of lysyl oxidase activity. There was also a high positive correlation (P less than 0.001) between cellular copper concentration and incorporation (r = 0.869). One of the two E-D IX patients was also shown to have similar changes in lysyl oxidase activity and collagen extractability in the skin biopsy specimen, suggesting that the abnormalities observed in cultured cells are similar to those present in vivo. The only distinct abnormality found in the cells of the parents of the E-D IX patients was an increased 64Cu incorporation in those of the mother, this finding being consistent with X-linked inheritance of the disorder.
 ...
PMID:Alterations in copper and collagen metabolism in the Menkes syndrome and a new subtype of the Ehlers-Danlos syndrome. 614 Sep 52

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.
 ...
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.
 ...
PMID:Metallothionein--aspects related to copper and zinc metabolism. 641 69

Menkes's syndrome (trichopoliodystrophy) is an x-linked, recessive genodermatosis characterized by hair defects, severe retardation, convulsions, progressive neurologic deterioration, and early death. Recent studies in copper metabolism suggest that Menkes's syndrome may be a storage disease in which copper is irreversibly trapped in some tissues by metallothionein, a heavy-metal-binding protein. This then gives rise to a deficiency elsewhere, particularly in the brain, causing irreversible damage in the fetus. We present a patient with Menkes's syndrome and review the clinical and metabolic aspects of this disease.
 ...
PMID:Menkes's syndrome. 649 70


<< Previous 1 2 3 4 5 6 Next >>