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)

The kinky hair syndrome (KHS) is an X-linked defect of copper transport in man. An animal model is available in mutants at the X-linked mottled locus in mice. The defect does not involve the uptake of copper from the intestinal lumen but rather the transport of copper from intestinal cells. The reduced activity of several copper-dependent enzymes and the lower copper content of serum, liver, and probably brain account for the manifestations of the disorder which are evident at, or shortly after, birth. Intrauterine involvement is likely but prenatal diagnosis is not yet possible. Although the delivery of iron to the erythropoietic system, and its utilization, are impaired in nutritionally induced copper deficiency, as is neutrophil production, these processes appear normal in KHS. thus, adequate copper to carry them out is available in KHS. While there may be more than one transport system for copper (only one of which is affected in KHS) it is also possible that the hematopoietic tissue in KHS, like the intestinal cells, has abnormally high afficity for copper. The presence of multiple alleles at the KHS locus (and at other genetic loci) in man, which cause different degrees of reduction in copper transport, could account for variations in the susceptibility to copper deficiency observed in infant populations.
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PMID:Menkes' kinky hair syndrome: a genetic disease involving copper. 82 88

The macular mottled mouse is a murine model of the kinky hair syndrome, characterized by a deficiency in copper transport. Cytochrome c oxidase (CCO), a respiratory enzyme, is located in the inner mitochondrial membrane and consists of seven subunits, along with copper and iron. Biochemical and histochemical findings indicated that CCO activity was decreased in the cerebellum of the macular mottled mice but not in that of the controls. Immunocytochemical analysis, using anti-CCO and anti-complex III rabbit sera, revealed that CCO in the macular mottled mice was stained more weakly than that in the controls. Immuno-electron microscopic examination of CCO and complex III, using a method of gold labeling, was also performed. In the control mice, a high concentration of gold particles present over CCO and complex III could be seen in the inner mitochondrial membrane. The number of CCO-labeled gold particles was remarkably less, however, in the macular mottled mice, while no significant difference was found in the labeling of complex III between the two groups. It may be concluded that the very low CCO enzyme content in the macular mottled mouse results not only from a copper transport disorder but also from a CCO protein synthesis disorder which impairs the localization of CCO protein in the cerebellum.
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PMID:Decreased activity of cytochrome c oxidase in the macular mottled mouse: an immuno-electron microscopic study. 254 95

Female C57BL mice heterozygous for the brindled gene were mated to normal males and fed on a purified diet low in copper throughout gestation and lactation with (+Cu) or without (-Cu) Cu-supplemented drinking water. Male offspring of two genotypes (control, +/y and brindled, Mobr/y) were compared when 10-12 d old. Brindled mice from dams on the -Cu treatment were smaller and had lower packed cell volumes than brindled mice from dams on the +Cu treatment. The -Cu brindled mice were smaller than their littermate brothers (+/y) but had equivalent biochemical features consistent with severe Cu deficiency. Compared with control mice from dams on the +Cu treatment, caeruloplasmin (EC 1.16.3.1) activity was lower in offspring of all three other groups including Mobr/y mice who were not anaemic. Iron levels were similar in organs and bone marrow from all four groups of offspring. When dietary Cu is limiting in brindled mice a more severe Cu deficiency ensues. Thus, appropriate Cu nutriture is important to the management of Menkes' disease in humans, a genetic analogue of the brindled mouse.
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PMID:Effects of dietary copper deficiency on male offspring of heterozygous brindled mice. 278 80

Copper is an essential trace element that is required for a number of enzymes which are necessary for normal metabolic function. Metabolic balance studies have demonstrated that daily copper losses are approximately 1.3 mg/day. In order to remain in copper balance, the average adult male must consume a diet which contains at least 2 mg copper/day. It has been assumed that most diets satisfy this requirement because of the ubiquitous presence of copper in most foodstuffs. Recent studies, however, have shown that dietary copper may often fall below the estimated daily needs. Nevertheless, clinically evident copper deficiency has been documented in only a few situations. Of these disorders. Menkes' syndrome has been most intensively studied. This x-linked abnormality is associated with copper deficiency due to impaired gastrointestinal copper absorption. However, the clinical disorder cannot be corrected readily with copper replacement, thus suggesting that Menkes' syndrome may reflect more than simple copper deficiency. Nutritional copper deficiency appears to be well documented in two situations: (1) the newborn, usually premature, undergoing rapid growth on a diet poor in copper, and (2) the patient maintained on total parenteral nutrition for long periods of time without copper supplementation. In both of these situations, anemia and neutropenia are the most striking hematologic abnormalities associated with copper deficiency. Sideroblastic changes as well as nuclear maturation defects observed in erythroid precursors. However, suggest that there is an effect of copper deficiency on the hematopoietic system which cannot be explained solely by defective plasma iron transport.
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PMID:Copper deficiency in humans. 641 May 10

The CCC2 gene of the yeast Saccharomyces cerevisiae is homologous to the human genes defective in Wilson disease and Menkes disease. A biochemical hallmark of these diseases is a deficiency of copper in ceruloplasmin and other copper proteins found in extracytosolic compartments. Here we demonstrate that disruption of the yeast CCC2 gene results in defects in respiration and iron uptake. These defects could be reversed by supplementing cells with copper, suggesting that CCC2 mutant cells were copper deficient. However, cytosolic copper levels and copper uptake were normal. Instead, CCC2 mutant cells lacked a copper-dependent oxidase activity associated with the extracytosolic domain of the FET3-encoded protein, a ceruloplasmin homologue previously shown to be necessary for high-affinity iron uptake in yeast. Copper restored oxidase activity both in vitro and in vivo, paralleling the ability of copper to restore respiration and iron uptake. These results suggest that the CCC2-encoded protein is required for the export of copper from the cytosol into an extracytosolic compartment, supporting the proposal that intracellular copper transport is impaired in Wilson disease and Menkes disease.
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PMID:The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-like oxidase required for iron uptake. 770 96

Animal and human studies have shown that copper is involved in the function of several enzymes. Studies have also shown that copper is required for infant growth, host defense mechanisms, bone strength, red and white cell maturation, iron transport, cholesterol and glucose metabolism, myocardial contractility, and brain development. Copper deficiency can result in the expression of an inherited defect such as Menkes syndrome or in an acquired condition. Acquired deficiency is mainly a pathology of infants; however, it has been diagnosed also in children and adults. Most cases of copper deficiency have been described in malnourished children. The most constant clinical manifestations of acquired copper deficiency are anemia, neutropenia, and bone abnormalities. Other, less frequent manifestations are hypopigmentation of the hair, hypotonia, impaired growth, increased incidence of infections, alterations of phagocytic capacity of the neutrophils, abnormalities of cholesterol and glucose metabolism, and cardiovascular alterations. Measurements of serum copper and ceruloplasmin concentrations are currently used to evaluate copper status. These indexes are diminished in severe to moderate copper deficiency; however, they are less sensitive to marginal copper deficiency. Erythrocyte superoxide dismutase and platelet cytochrome c activities may be more promising indexes for evaluating marginal copper deficiency.
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PMID:Copper as an essential nutrient. 861 66

Recent studies resulted in the cloning of the genes responsible for Menkes syndrome and Wilson disease. Despite the distinct clinical phenotypes of these disorders, each gene encodes a highly homologous member of the cation-transport P-type ATPase family. The remarkable evolutionary conservation of these proteins in bacteria, yeast, plants, and mammals reveals a fundamental protein structure essential for copper export in all life forms. Characterization of a molecular defect in the rat homologue of the Wilson ATPase in the Long-Evans Cinnamon rat identifies an animal model of Wilson disease and will permit experimental analysis of the precise role of this ATPase in copper transport, the effects of specific inherited mutations on transport function, and the cellular and molecular mechanisms of tissue injury resulting from copper accumulation. Finally, recent molecular genetic analysis of a distinct group of patients with low serum ceruloplasmin and basal ganglia symptoms identified a series of mutations in the ceruloplasmin gene. The presence of these mutations in conjunction with the clinical and pathologic findings clarifies the essential biological role of this abundant copper protein in metal metabolism and identifies aceruloplasminemia as a novel autosomal recessive disorder of iron metabolism.
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PMID:Genetic and molecular basis for copper toxicity. 861 71

The molecular mechanisms responsible for the cellular uptake of copper in mammalian cells are unknown. We describe isolation of a human gene involved in this process by complementation of the yeast high-affinity copper uptake mutant, ctr1. Besides complementing ctr1 growth defect on nonfermentable media, the human gene also rescues iron transport and SOD1 defects in ctr1 yeast. Overexpression of the gene in yeast leads to vulnerability to the toxicity of copper overload. In addition, its expression in ctr1 yeast significantly increases the level of cellular copper, as demonstrated by atomic absorption. We propose this gene as a candidate for high-affinity copper uptake in humans and by analogy have named it hCTR1. The hCTR1 and yeast CTR1 predicted transmembrane proteins are 29% identical, but the human protein is substantially smaller in both the extracellular metal-binding and intracellular domains. An additional human gene similar to hCTR1, here named hCTR2, was identified in a database search. Both hCTR1 and hCTR2 are expressed in all human tissues examined, and both genes are located in 9q31/32. These studies, together with the previously recognized functional and sequence similarity between the Menkes/Wilson copper export proteins and CCC2 in yeast, demonstrate that similar copper homeostatic mechanisms are used in these evolutionarily divergent organisms.
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PMID:hCTR1: a human gene for copper uptake identified by complementation in yeast. 920 17

A defect in the yeast GEF1 gene, a CLC chloride channel homolog leads to an iron requirement and cation sensitivity. The iron requirement is due to a failure to load Cu2+ onto a component of the iron uptake system, Fet3. This process, which requires both Gef1 and the Menkes disease Cu2+-ATPase yeast homolog Ccc2, occurs in late- or post-Golgi vesicles, where Gef1 and Ccc2 are localized. The defects of gef1 mutants can be suppressed by the introduction of Torpedo marmorata CLC-0 or Arabidopsis thaliana CLC-c and -d chloride channel genes. The functions of Gef1 in cation homeostasis provide clues to the understanding of diseases caused by chloride channel mutations in humans and cation toxicity in plants.
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PMID:The yeast CLC chloride channel functions in cation homeostasis. 952 Apr 90

The role of trace elements in vivo has not been completely clarified. Trace elements were studied in melanin granules in the retinal pigment epithelium (RPE) and choroid of hereditary copper-deficient macular mice as a model of Menkes' disease. The analysis of elements in these melanin granules was done by new methods: freeze-embedding and an energy dispersive X-ray microanalysis (EDX). We used 14-day- and 1-month-old male hemizygote macular mice for the experiments and normal litter-mates as controls. Melanin granules in RPE and choroid contained sulfur, chloride, calcium, iron, copper and zinc. Calcium and copper were especially abundant in 14-day-old hemizygote macular mice, although there were few melanin granules in their RPE. The fact that copper was most abundant in the melanin granules in the RPE of 14-day-old macular mice suggests that the synthesis of melanin granules in the RPE and choroid of the hemizygote macular mice cannot be completed because of the lower activity of copper-containing enzymes such as tyrosinase and the abnormal copper distribution in various organs. Therefore, the melanin granules in the RPE and choroid of hemizygote macular mice are irregular in shape and few in number. Large amounts of copper concentrated in melanin granules in the RPE and choroid of hemizygote macular mice might induce quantitative abnormalities of trace elements.
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PMID:X-ray microanalysis of melanin granules of retinal pigment epithelium and choroid in hereditary copper deficient mice (macular mice). 998 42


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