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 mottled mouse has been proposed as an animal model for Menkes disease, an X-linked disorder of copper transport. The recent isolation of a copper-transporting ATPase gene responsible for Menkes disease has allowed us to test this hypothesis. Here we report the isolation and sequence of the mouse homologue of this gene. We show that two mottled (Mo) alleles, dappled (Modp) and blotchy (Moblo), have abnormalities in the murine mRNA and that Modp has a partial gene deletion. These studies prove that the mottled mouse is the murine model for Menkes disease, providing the basis for future biochemical and therapeutic studies.
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PMID:The mottled gene is the mouse homologue of the Menkes disease gene. 772 11

Little is known at the molecular level about the homeostatic control of heavy-metal concentrations in mammals. Recently, however, two human diseases that disrupt copper transport, Menkes disease and Wilson disease, were found to be caused by mutations in two closely related genes, MNK and WND, which encode proteins belonging to the P-type ATPase family of cation transporters. The MNK and WND proteins are unique in having at their amino termini six copies of a sequence that is remarkably similar to sequences previously found in bacterial heavy-metal-resistance proteins and in a P-type ATPase that appears to form part of a bacterial copper homeostatic system. These two human ATPases are the first putative heavy-metal transporters to be discovered in eukaryotes.
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PMID:Wilson disease and Menkes disease: new handles on heavy-metal transport. 809 5

The putative copper and ATP-binding domains of the human Menkes disease gene were used as probes to screen a human liver cDNA library at reduced stringency. Sixty-five clones which remained positive after tertiary screening were subcloned and sequenced. One of these cDNA clones contains an open reading frame with 65% amino acid homology to the Menkes protein. Southern blot analysis localizes this cDNA to the region of the Wilson disease locus on chromosome 13. This cDNA detects a 7.5 kB transcript which is present in human liver and cell lines devoid of the Menkes transcript and which is absent in liver from a patient with Wilson disease. These data suggest that this cDNA is a candidate gene for Wilson disease and that the protein encoded at this locus is a member of the P-type ATPase family.
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PMID:Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. 825 Sep 34

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P-type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.
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PMID:The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. 829 39

Although the causes of the abnormal copper utilization seen in Menkes' disease remain unknown, a candidate gene reported by three laboratories has narrowed the search for the defective or missing factor. These genetic studies also suggest that a copper ATPase may be important in normal copper metabolism.
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PMID:Menkes' disease: perspective and update on a fatal copper disorder. 830 93

Menkes disease is an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty-one Menkes patients. Four patients lacking Mc1RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P-type cation-transporting ATPase. The gene product is most similar to a bacterial copper-transporting ATPase and additionally contains six putative metal-binding motifs at the N-terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.
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PMID:Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. 849 Jun 49

To correlate genotype with response to early copper histidine therapy in Menkes disease, an X-linked disorder of copper transport, we performed mutational analysis in 2 related males who began treatment at the age of 10 days and prenatally at 32 weeks' gestation, respectively. A G to T transversion at the -1 exonic position of a splice donor site was identified, predicting a glutamine to histidine substitution at codon 724 of the Menkes copper-transporting ATPase gene. The Q724H mutation disrupts proper splicing and generates five mutant transcripts that skip from one to four exons. None of these transcripts is predicted to encode a functional copper transport protein. Copper histidine treatment normalized circulating copper and ceruloplasmin levels but did not improve the baseline deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. At the age of 36 months, the first patient was living and had neurodevelopmental abilities ranging from 10 to 15 months. The second patient also showed delayed neurodevelopment and died of pulmonary complications at the age of 5 1/2 months. We conclude that early copper histidine therapy does not normalize neurological outcome in patients with the Q724H splicing mutation, and suggest that preservation of some residual Menkes ATPase activity may be a general prerequisite for significant clinical efficacy from such treatment.
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PMID:Early copper therapy in classic Menkes disease patients with a novel splicing mutation. 900 80

Cellular copper transport processes are required by all organisms for correct utilization in cell biochemical processes and avoidance of the toxicity of copper excess. Copper import into bacterial, yeast, and mammalian cells requires the coordinate function of proteins with both metal-binding and catalytic domains in mediated transport steps. Following entry, detoxification mechanisms found across species include the binding of copper to specific proteins (e.g. metallothioneins) and the transfer of copper into isolated cell compartments (e.g. periplasmic space, lysosome). Multiple proteins mediate intracellular transfers in bacteria, and glutathione may play a major role in cytosolic copper delivery to cuproenzymes in mammalian cells. Study of two human disorders of copper transport, Menkes disease and Wilson disease, led to the identification of an important category of proteins mediating cell copper export. The Menkes and Wilson disease gene products are copper-transporting ATPases of the P type, with ATPase domains and N-terminal metal-binding amino acid motifs that are evolutionarily conserved in unicellular and mammalian organisms. These observations suggest that yeast and bacterial copper transport proteins, or individual domains of these proteins, may generally have homologues in mammalian systems.
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PMID:Cellular copper transport. 852 22

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

Human Menkes disease and the murine Mottled phenotype are X-linked diseases that result from copper deficiency due to mutations in a copper-effluxing ATPase, designated ATP7A. Male mice with the Mottled-Brindled allele (Mo-brJ) accumulate copper in the intestine, fail to export copper to peripheral organs and die a few weeks after birth. Much of the intestinal copper is bound by metallothionein (MT). To determine the function of MT in the presence of Atp7a deficiency, we crossed Mo-brJ females with males that bear a targeted disruption of the Mt1 and Mt2 genes (Mt-/-). On an Mt -/- background, most Mo-brJ males as well as heterozygous Mo-brJ females die before embryonic day 11. The lethality in Mo-brJ females can be explained by preferential inactivation of the paternal X chromosome in extraembryonic tissues and resultant copper toxicity in the absence of MT. In support of this hypothesis, cell lines derived from Mt -/-, Mo-brJ embryos are very sensitive to copper toxicity.
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PMID:A murine model of Menkes disease reveals a physiological function of metallothionein. 864 Feb 30


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