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)

Menkes gene (Mc1 or MNK, encoding putative copper-transporting ATPase) expression was investigated and compared in normal and macular mutant mouse brain. Northern blot analysis showed a distinct 8.3-kb transcript and no obvious difference in size or extent in normal mice and macular mutants on postnatal days 0, 4, 7, 10 or 13. In situ hybridization revealed that certain specific populations of cells in the brain express Menkes mRNA, and that their localization in normal and mutant mice did not differ and was conserved on days 4, 10 and 13. The most intense hybridization signals were observed in the hippocampal CA1 region and dentate gyrus, the olfactory bulb nuclei, the cerebellar granular cell layer, the choroid plexus and the ependyma, with less intense signals in the hippocampal CA3 region and cerebellar Purkinje cells. In addition, necrotic neuronal cell death was predominantly observed in the CA3 region and the Purkinje cells of macular mice after postnatal day 10. The finding that the regions that had lower expression level of Menkes mRNA corresponded to those showing neuronal necrosis suggests that the Menkes gene may be responsible for the neuronal degeneration in some specific portions of the brain and clinical manifestations in this mutant.
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PMID:Localization of Menkes gene expression in the mouse brain; its association with neurological manifestations in Menkes model mice. 874 Feb 28

To define the function of the Cu-transporting ATPase in Menkes disease, Menkes and normal fibroblasts were incubated with 67Cu before and after brief exposure to -SH reagents, p-chloromercuribenzoate (PCMB) and dithiothreitol (DTT). Accumulation and retention were compared among these cells, BeWo cells, and rat C6 glioma cells similarly treated. The Michaelis constant for influx of 67Cu into normal and Menkes fibroblasts was practically the same (0.21 +/- 0.07 vs. 0.24 +/- 0.06 microM). The PCMB treatment stimulated 67Cu accumulation in C6 cells, inhibited accumulation in normal and Menkes fibroblasts, and did not affect BeWo cells. DTT stimulated 67Cu uptake in all cells but BeWo cells. DTT treatment after PCMB further enhanced 67Cu accumulation in normal fibroblasts and C6 cells but had no enhancing effect on Menkes fibroblasts or BeWo cells. Menkes fibroblasts and BeWo cells released 67Cu at rates considerably slower than normal fibroblasts (0.06 and 0.09 vs. 0.22%/min, respectively). The PCMB blocked 67Cu release from normal fibroblasts but did not affect Menkes fibroblasts or BeWo cells. Reverse transcription-polymerase chain reaction analysis of total RNA from BeWo cells failed to show a predicted 943-base pair fragment representing a partial transcript of the Menkes factor. The fragment was present in extracts from normal fibroblasts. We conclude that the mechanism underlying Cu homeostasis varies among different cell types. As exemplified by BeWo and Menkes cells, failure to efflux Cu ions may be linked with the failure to express a functional Cu-transporting ATPase, namely, the Menkes protein.
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PMID:Functional analysis of a genetic defect of copper transport (Menkes disease) in different cell lines. 876 68

Classical Menkes disease is a fatal X-linked neurodegenerative disorder caused by defects in a gene (MNK) that encodes a copper-transporting ATPase. Treatment with parenteral copper has been proposed for patients identified before symptoms develop. We recently described suboptimal outcomes despite early copper replacement in two classical Menkes patients whose mutation predicts little if any functional copper transporter. Here, we describe successful copper replacement therapy in a patient with Menkes disease with a splice acceptor site mutation (IVS8,AS,dup5) that causes exon-skipping and generates a mutant transcript with a small in-frame deletion in a noncritical region. The patient was diagnosed by analysis of neurochemical levels in cord blood, and parenteral copper replacement was begun at 8 days of life. Throughout infancy, he showed normal head growth, brain myelination, and age-appropriate neurodevelopment, including independent walking at 14 months of age. In contrast, his affected half-brother and first cousin with the same mutation, but who were not diagnosed and treated from an early age, showed arrested head growth, cerebral atrophy, delayed myelination, and abnormal neurodevelopment. We propose that the successful neurological outcome in this patient was related to early repletion of circulating copper levels, in combination with residual copper transport by a partially functional MNK ATPase containing the small deletion. We hypothesize that raising plasma copper concentrations in patients with Menkes disease with some residual functional gene product can increase the ligand: transporter ratio and thus alter favorably the kinetics of copper transport into and within the brain.
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PMID:Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small In-frame deletion. 881 25

Bacterial plasmids encode resistance systems for toxic metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, CO2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+, and Zn2+. In addition to understanding of the molecular genetics and environmental roles of these resistances, studies during the last few years have provided surprises and new biochemical mechanisms. Chromosomal determinants of toxic metal resistances are known, and the distinction between plasmid resistances and those from chromosomal genes has blurred, because for some metals (notably mercury and arsenic), the plasmid and chromosomal determinants are basically the same. Other systems, such as copper transport ATPases and metallothionein cation-binding proteins, are only known from chromosomal genes. The largest group of metal resistance systems function by energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The CadA cadmium resistance ATPase of gram-positive bacteria and the CopB copper efflux system of Enterococcus hirae are homologous to P-type ATPases of animals and plants. The CadA ATPase protein has been labeled with 32P from gamma-32P-ATP and drives ATP-dependent Cd2+ uptake by inside-out membrane vesicles. Recently isolated genes defective in the human hereditary diseases of copper metabolism, Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to the bacterial CadA and CopB ATPases than to eukaryote ATPases that pump different cations. The arsenic resistance efflux system transports arsenite, using alternatively either a two-component (ArsA and ArsB) ATPase or a single polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As (V)] to arsenite [As (III)], the substrate of the efflux system. The three-component Czc (Cd2+, Zn2+, and CO2+) chemiosmotic efflux pump of soil microbes consists of inner membrane (CzcA), outer membrane (CzcC), and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell. Finally, the first bacterial metallothionein (which by definition is a small protein that binds metal cations by means of numerous cysteine thiolates) has been characterized in cyanobacteria.
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PMID:Bacterial heavy metal resistance: new surprises. 890 98

Occipital horn syndrome (OHS), an X-linked connective tissue disorder, has recently been shown to result from mutations in the Menkes disease gene (MNK), which encodes a copper-transporting ATPase. By Southern analysis we detected a small deletion in a region 5' to the MNK gene in one patient with OHS. Genomic clones from an unaffected individual were isolated and sequenced, revealing three tandem 98 bp repeats situated upstream of the reported transcription start site, and analysis of the patient's DNA showed a deletion of one of the repeats. The deletion is likely to be responsible for the disease in this patient, as it was not observed in 110 unaffected individuals analyzed, and no other mutation in the patient was detected by RT-PCR and chemical cleavage mismatch analysis or by cDNA sequence analysis. The deletion is associated with a dramatic decrease in expression of a chloramphenicol acetyltransferase reporter gene, implicating the repeat sequences in regulation of MNK expression, although a quantitative analysis of MNK mRNA from a cell line derived from the patient shows no detectable reduction. Other experiments revealed no effect on the site of transcription initiation, termination or on splicing.
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PMID:A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome. 892 1

Menkes disease is a fatal neurodegenerative disorder of childhood due to the absence or dysfunction of a putative copper-transporting P-type ATPase encoded on the X chromosome. To elucidate the biosynthesis and subcellular localization of this protein, polyclonal antisera were generated against a bacterial fusion protein encoding the 4th to 6th copper-binding domains in the amino terminus of the human Menkes protein. RNA blot analysis revealed abundant Menkes gene expression in several cell lines, and immunoblotting studies utilizing this antiserum readily detected a 178-kDa protein in lysates from these cells. Pulse-chase studies indicate that this protein is synthesized as a single-chain polypeptide which is modified by N-linked glycosylation to a mature endoglycosidase H-resistant form. Sucrose gradient fractionation of HeLa cell lysates followed by immunoblotting of individual fractions with antibodies to proteins of known intracellular location identified the Menkes ATPase in fractions similar to those containing the cation-independent mannose-6-phosphate receptor. Consistent with this observation, confocal immunofluorescence studies of these same cells localized this protein to the trans-Golgi network and a vesicular compartment with no expression in the nucleus or on the plasma membrane. Taken together, these data provide a unique model of copper transport into the secretory pathway of mammalian cells which is compatible with clinical observations in affected patients and with recent data on homologous proteins identified in prokaryotes and yeast.
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PMID:Biochemical characterization and intracellular localization of the Menkes disease protein. 894 55

The Menkes P-type ATPase (MNK), encoded by the Menkes gene (MNK; ATP7A), is a transmembrane copper-translocating pump which is defective in the human disorder of copper metabolism, Menkes disease. Recent evidence that the MNK P-type ATPase has a role in copper efflux has come from studies using copper-resistant variants of cultured Chinese hamster ovary (CHO) cells. These variants have MNK gene amplification and consequently overexpress MNK, the extents of which correlate with the degree of elevated copper efflux. Here, we report on the localization of MNK in these copper-resistant CHO cells when cultured in different levels of copper. Immunofluorescence studies demonstrated that MNK is predominantly localized to the Golgi apparatus of cells in basal medium. In elevated copper conditions there was a rapid trafficking of MNK from the Golgi to the plasma membrane. This shift in steady-state distribution of MNK was reversible and not dependent on new protein synthesis. In media containing basal copper, MNK accumulated in cytoplasmic vesicles after treatment of cells with a variety of agents that inhibit endosomal recycling. We suggest that MNK continuously recycles between the Golgi and the plasma membrane and elevated copper shifts the steady-state distribution from the Golgi to the plasma membrane. These data reveal a novel system of regulated protein trafficking which ultimately leads to the efflux of an essential yet potentially toxic ligand, where the ligand itself appears directly and specifically to stimulate the trafficking of its own transporter.
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PMID:Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. 894 31

Wilson disease is a rare autosomal recessive disease of copper metabolism. The gene for Wilson disease was characterized recently and has been predicted to encode a copper-transporting ATPase highly homologous to the protein encoded by the gene of Menkes disease. In this study, the genetic mutations of two Finnish patients with Wilson disease were investigated. One patient was homozygous for a novel nonsense mutation in exon 4, while the other was a compound heterozygote. Lysyl oxidase (EC 1.4.3.13) is an extracellular copper enzyme with deficient activity in Menkes disease. The levels of lysyl oxidase activity in cultured skin fibroblasts from these Wilson disease patients were also measured.
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PMID:A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. 898 Feb 83

Genomic DNA of 41 unrelated patients affected with the classical severe form of Menkes disease was investigated for point mutations in the ATP7A gene (previously designated as the "MNK" gene). Using SSCP analysis and direct sequencing of the exons amplified by PCR, we identified 41 different mutations, including 19 insertions/deletions, 10 nonsense mutations, 4 missense mutations, and 8 splice-site alterations. Approximately 90% of the mutations were predicted to result in the truncation of the protein (ATP7A). In 20 patients the mutations were within exons 7-10, and half of these mutations affected exon 8. Furthermore, five alterations were observed within the 6-bp sequence at the splice-donor site of intron 8, which would be predicted to affect the efficiency of splicing of exon 8. Although a specific function has not been attributed to the protein region encoded by this exon, this region may be important in serving as a "stalk" joining the metal-binding domains and the ATPase core. The present findings not only help us in understanding the underlying genetic defect but are invaluable data especially for carrier detection and prenatal diagnosis of this lethal disorder.
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PMID:Identification of point mutations in 41 unrelated patients affected with Menkes disease. 898 48

Bacterial plasmids encode resistance systems for toxic metal ions, including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+ and Zn2+. The function of most resistance systems is based on the energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The Cd(2+)-resistance ATPase of Gram-positive bacteria (CadA) is membrane cation pump homologous with other bacterial, animal and plant P-type ATPases. CadA has been labeled with 32P from [alpha-32P] ATP and drives ATP-dependent Cd2+ (and Zn2+) uptake by inside-out membrane vesicles (equivalent to efflux from whole cells). Recently, isolated genes defective in the human hereditary diseases of copper metabolism, namely Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to bacterial CadA than to other ATPases from eukaryotes. The arsenic resistance efflux system transports arsenite [As(III)], alternatively using either a double-polypeptide (ArsA and ArsB) ATPase or a single-polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. The triple-polypeptide Czc (Cd2+, Zn2+ and Co2+) chemiosmotic efflux pump consists of inner membrane (CzcA), outer membrane (CzcC) and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell.
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PMID:Bacterial resistances to toxic metal ions--a review. 899 52


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