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)

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

We report a detailed molecular analysis of the genomic structure of the Menkes disease gene (MNK; ATP7A). There are 23 exons in ATP7A covering a genomic region of approximately 140 kb. The size of the individual coding exons varies between 77 and 726 bp, and introns vary in size between 196 bp and approximately 60 kb. All of the splice sites obey the consensus GT-AG rule except the splice donor of intron 9, which is GC instead of GT. The exon following this rare splice donor variant is alternatively spliced. A PGAM pseudogene and two highly polymorphic CA repeats map to introns within the gene. The structure is very similar to that of the closely related Wilson disease gene (WND; ATP7B). From exon 5 (exon 3 in ATP7B) to the end, all of the splice sites occur at exactly the same nucleotide positions as in the WND gene, except for the boundary between exons 17 and 18 (exons 15 and 16 in ATP7B) and a single codon difference at the boundary between exons 4 and 5 of the MNK gene (exons 2 and 3 in ATP7B). In contrast to the WND gene, in which the first four of six metal binding domains are contained in 1 exon, metal binding domains 1 to 4 are divided over 3 exons. The striking similarity of the MNK and WND genes at the genomic level is consistent with their relatively recent divergence from a common ancestral gene.
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PMID:Molecular structure of the Menkes disease gene (ATP7A). 749 81

Tetracycline (TC) exerts DNA damaging properties which are accelerated in the presence of copper(II). Thereby, reactive oxygen species are generated. We investigated, if copper-accumulating cells show a higher sensitivity to TC compared to normal cells. Fibroblasts with an increased copper content were derived from patients of two genetic disorders, Wilson disease (WD) and Menkes disease (MD). Cytotoxic and genotoxic effects of TC were investigated in different human fibroblasts. The inhibition of cell growth by TC was measured in two normal fibroblast lines, fibroblast lines of two patients with WD and one patient with MD. While TC inhibited cell growth at similar concentrations in normal fibroblasts and the MD fibroblasts, the WD cells were much more sensitive. Furthermore, an increased inhibition of DNA synthesis and an enhanced induction of unscheduled DNA synthesis (UDS) was found in WD cells after a TC-treatment compared to normal cells.
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PMID:Enhanced cyto- and genotoxicity of tetracycline in Wilson disease fibroblasts. 756 16

The gene defective in Menkes disease, an X-linked recessive disturbance of copper metabolism, has been isolated and predicted to encode a copper-binding P-type ATPase. We determined the complete exon-intron structure of the Menkes disease gene, which spans about 150 kb of genomic DNA. The gene contains 23 exons, and the ATG start codon is in the second exon. All of the exon-intron boundaries were sequenced and conformed to the GT/AT rule, except for the 5' splice site of intron 9. A preliminary comparison demonstrated a striking similarity between the exon structures of the Menkes and Wilson disease genes, giving insight into their evolution.
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PMID:Characterization of the exon structure of the Menkes disease gene using vectorette PCR. 760 65

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

Neuromedin C is a bombesin-like neuropeptide of the sequence Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2. Characterization of the amino terminal Cu(II), Ni(II) binding motif in albumins led us to predict that any other peptides or proteins with the same motif would also bind Cu(II) and Ni(II) specifically (1). The primary sequence of neuromedin C contains the motif in the form Gly-Asn-His. Neuromedin C was therefore predicted to bind Cu(II) and Ni(II) specifically. The studies presented here confirm that prediction. These findings may have implications for the transport of Cu(II) within the central nervous system as well as both Menkes disease and Wilson disease. Both are genetic copper metabolism disorders which are characterized by severe neurological symptoms. In addition, Cu(II) may interfere with the neurotransmission or growth factor effects of neuromedin C.
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PMID:Neuromedin C binds Cu(II) and Ni(II) via the ATCUN motif: implications for the CNS and cancer growth. 773 79

We have isolated, sequenced, mapped and disrupted a gene, CCC2, from Saccharomyces cerevisiae. This gene displays non-allelic complementation of the Ca(2+)-sensitive phenotype conferred by the csg1 mutation. Analysis of the CCC2p amino acid sequence reveals that it encodes a member of the P-type ATPase family and is most similar to a subfamily thought to consist of Cu2+ transporters, including the human genes that mutate to cause Wilson disease and Menkes disease. The ability of this gene, in two or more copies, to reverse the csg1 defect suggests that Ca(2+)-induced death of csg1 mutant cells is related to Cu2+ metabolism. Cells without CCC2 require increased Cu2+ concentrations for growth. Therefore CCC2p may function to provide Cu2+ to a cellular compartment rather than in removal of excess Cu2+.
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PMID:Sequence, mapping and disruption of CCC2, a gene that cross-complements the Ca(2+)-sensitive phenotype of csg1 mutants and encodes a P-type ATPase belonging to the Cu(2+)-ATPase subfamily. 778 28

Menkes disease and Wilson disease are human disorders of copper metabolism. It has recently been shown that both are due to mutations in P-type ATPase copper transport molecules. Related heavy metal transporting ATPases have been described in several strains of bacteria. In an effort to isolate other mammalian metal transporters, we screened a human small intestine library with probes homologous to conserved sequences in the known proteins. Two novel cDNAs were isolated, which encode new members of this family. Surprisingly, they were both of bacterial origin, most likely derived from E. coli sequences transduced during library construction.
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PMID:Novel bacterial P-type ATPases with histidine-rich heavy-metal-associated sequences. 781 Dec 48

Menkes disease is an X linked recessive disorder of copper metabolism characterised by neurological symptoms and connective tissue manifestations. The defective gene in Menkes disease has recently been isolated and the gene product is predicted to be a copper transporting ATPase. The diagnosis of Menkes disease has hitherto been performed by biochemical analysis, based on intracellular accumulation of copper. Cloning the gene opened up the possibility of establishing precise and reliable carrier and prenatal diagnosis by defining the molecular defect. In this report we describe the partial deletion of the Menkes gene in a patient who had inherited the mutation from his phenotypically normal mother. This information enabled us to perform prenatal diagnosis by direct mutation analysis of the mother's sixth pregnancy and we detected the same deletion, indicating that the male fetus was affected. This first prenatal diagnosis of Menkes disease by direct mutation analysis shows some advantages of DNA analysis compared to biochemical diagnosis.
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PMID:First trimester prenatal diagnosis of Menkes disease by DNA analysis. 781 18

Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver.
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PMID:Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. 783 24


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