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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The macular mouse is a mutant mouse with a defect in copper transport and an X-linked recessive inheritance. Its hemizygote (Ml/y) is considered to be an appropriate model fo Menkes kinky hair disease (MKHD). In this study, homozygote (Ml/Ml) were bred by coupling CuCl2-treated Ml/y with heterozygote (Ml/+). Both Ml/Ml and Ml/y die around day 15 of age. However, treatment with CuCl2 enables them to live until adulthood. The brains of Ml/Ml were chronologically examined by light and electron microscopy. In the non-treated Ml/Ml, abnormal mitochondria increased in number in the cerebral cortical neurons and in the cerebellar Purkinje cells from day 7 to 14 of age. In the treated Ml/Ml, the administration of CuCl2 improved the abnormality of the mitochondria in the cerebrum by day 20, but those in the Purkinje cells remained until day 60. Flattened cisterns and intracytoplasmic inclusions were also observed in the Purkinje cells of treated Ml/Ml. These ultrastructural changes were quite similar to those observed in the Ml/y. Our mutant mice (treated Ml/Ml), when they are coupled with treated Ml/y, can give birth to offspring, all of which will be genetically Ml/y or Ml/Ml. These fetal mice will be very helpful for studying the pathological and biochemical condition of prenatal MKHD.
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PMID:Electron microscopic study on the homozygote (Ml/Ml) of the macular mutant mouse. 228 83

Three female patients with Menkes syndrome are described. Clinically, they have typical Menkes syndrome. Biochemically, they have significantly increased 64Cu-uptake in cultured fibroblasts. The chromosomal analysis was normal for two of the patients and abnormal for one patient (45X/46XX mosaicism).
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PMID:Clinical expression of Menkes syndrome in females. 228 18

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

Menkes' kinky hair syndrome (KHS) is a lethal x-linked neurodegenerative disorder of copper metabolism, with low serum copper concentrations, tissue-specific copper sequestration, and decreased activities of cuproenzymes in a number of cell types. Although liver copper accumulation is abnormal in KHS, the actual defect in hepatic copper metabolism has not been elucidated. Our studies of liver copper metabolism were conducted in the mottled (blotchy) mouse, an animal model of KHS. After implantation of central venous and biliary catheters in both blotchy and control mice, we measured biliary copper excretion, hepatic copper uptake, and tissue copper contents over an 8-h period after i.v. bolus administration of radioactive 64Cu. Under the experimental conditions used, bile flow and biliary bile acid excretion were held constant, and control and blotchy hepatic 64Cu concentrations were similar in the face of the expected differential in control and mutant kidney 64Cu contents. Biliary excretion of radiocopper was 24.7 +/- 1.5% of injected 64Cu over 8 h in control animals, whereas heterozygotes excreted 6.5 +/- 1.3% and a single hemizygote excreted less than 2%. The pattern of biliary copper excretion was different, with sharp increase and steady decline in control biliary 64Cu excretion but consistently low excretion in mutant mice. No differences were observed in control or mutant hepatic uptake of 64Cu. These data show a reduced biliary excretion of copper in the blotchy mouse, in the absence of a defect in hepatic copper uptake. We suggest that defective copper transport from hepatocyte to bile represents the hepatic expression of the mottled mutation and speculate that a similar defect occurs in human KHS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic copper metabolism in a mouse model for Menkes' kinky hair syndrome. 234 76

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

Effects of chelators on the copper(Cu) therapy for the mutant mouse, Macular, which is a model animal of Menkes' disease were studied. Simultaneous administration of some chelators reduced the necessary dose of Cu (10 mg/kg) for the survival of the mice to one tenth. By this treatment the Cu concentration in the brain was increased but Cu in the kidney was not increased as much as Cu administration without chelator. Surviving mice showed normal growth in terms of body weight and fertility. Furthermore same effects were observed even when the chelator was administered without Cu. In the chelators tested, derivatives of carbamic acid like dimethyldithiocarbamate, which forms a lipophilic complex with Cu, were effective.
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PMID:Effects of chelators on copper therapy of macular mouse, a model animal of Menkes' kinky disease. 239 48

A male infant with an atypical form of Menkes kinky hair disease showed mitochondrial NADH-CoQ reductase (complex I) deficiency in a femoris muscle biopsy. His clinical features consisted of hypotonicity of the upper limbs, hyper-reflexia of the lower extremities, abnormal hair and fine myoclonic movement of the hands. The serum levels of copper and ceruloplasmin were just below normal range, and the copper concentration in fibroblastic cells was much increased (101.2 ng/mg of protein). The occurrence of this case suggests that there may be a mild form of Menkes disease with a NADH-CoQ reductase deficiency or other mitochondrial enzyme defects.
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PMID:Atypical form of Menkes kinky hair disease with mitochondrial NADH-CoQ reductase deficiency. 245 75

The wet weights, contents of DNA, RNA and protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) activities were examined in the cerebrum, brain stem and cerebellum from macular mutant mouse, as a model animal for Menkes' kinky hair disease (MKHD). The DNA, RNA and protein contents in the cerebellum from macular hemizygous males (Ml/y) were affected to a much greater extent than those in the cerebrum and the brain stem. This suggests that the main affected part of the brain in Ml/y mouse is the cerebellum. CNP activities in the Ml/y mouse showed a significant decrease in every part of the brain after day 10. This finding may coincide with the changes in myelination in human MKHD.
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PMID:Biochemical study on the brain of the macular mutant mouse as a model of Menkes' kinky hair disease. 245 26

This study was undertaken to elucidate the clinical and neuropathological effects of copper administration on the macular mutant mouse. Its hemizygote, which is considered to be a model of Menkes kinky hair disease (MKHD), was injected intraperitoneally four times with 10, 20, 20 and 30 micrograms of cupric chloride on days 4, 6, 8 and 10, respectively. The hemizygote's curly whiskers gradually straightened and the frequent tonic seizures and ataxia disappeared after the injections. The body weight also gradually increased. In the cerebral cortex, the dendritic arborization of the pyramidal neurons in both the normal littermate and the treated hemizygote developed with time and reached the maximum around day 60. In the treated hemizygote, however, the arborization of the dendrites was significantly poor in comparison with that in the normal littermate from day 20 to 90. In the cerebellum of the treated hemizygote, the abnormal Purkinje cells with the few somal sprouts, thick stem dendrite and/or poor arborization, which were seen in the non-treated hemizygote, were improved by day 30, while their focal dendritic swellings remained even on day 60. These results indicate that the copper therapy improves not only the clinical manifestations but also the neuropathological changes, especially in the cerebellum.
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PMID:Golgi study on macular mutant mouse after copper therapy. 246 25

Both deficiency and excess of copper induce toxic effects on mammalian cell systems in vivo and in vitro. The effects can be related to the affinities of Cu(II) ions for specific cell components. The nucleus is a potential site for temporary Cu storage while primary targets for free Cu(II) ions are the thiol groups which reduce the ions to Cu(I). Cu(II) ions show a high affinity for nucleic acids, binding with DNA both at intrastrand and interstrand levels, possibly through intercalation between GC pairs. The ability to chelate Cu(II) ions is seen to be of the order: purine greater than purine ribonucleotides greater than purine ribonucleoside greater than pyrimidine ribonucleotides. Copper is an integral part of enzyme activation and enters into the molecular structure of several proteins, like ceruloplasmin. Cu(II) ion is a potential mutagenic agent as seen by its property of inducing infidelity in DNA synthesis in vitro. Teratogenic activities of copper have been reported but carcinogenicity is not yet confirmed. Copper is an essential component of chromatin and is known to accumulate preferentially in the heterochromatic regions. External application of higher doses, however, induces both clastogenic effects and spindle disturbances. In certain forms, inorganic copper enhances the clastogenic activity of other agents. The most widely studied human genetic maladies linked with copper metabolism are Menkes' and Wilson's diseases. Several mutations are known which influence Cu homeostasis in mammals. Such mutations in mice have been used extensively for biochemical studies.
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PMID:Effects of copper on mammalian cell components. 246 42


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