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 Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. Considerable clinical and genetic heterogeneity exists, and more than nine separate forms have been recognized. Recent advances in the molecular analysis of EDS have identify defects responsible for EDS VI (homozygous and compound heterozygous mutations in the lysyl-hydroxylase gene), EDS VIIA and EDS VIIB (mutations in the type I collagene genes), EDS VIIC (deficiency of procollagen N-proteinase), EDS IX (mutations in the MNK gene), and EDS IV (mutations in the type III collagen gene). Of the various types of Ehlers-Danlos syndrome the most severe is type IV (EDS IV). Early studies showed that fibroblasts from EDS IV patients secreted lower than normal amounts of type III procollagen (Pope et al., 1975). Later, the disease was linked to COL3A1, the gene encoding this protein. More recently, with the publication of full length cDNA and partial characterisation of the gene structure, detailed analysis of mutations in EDS IV patients has become possible. Nineteen different mutations in the type III procollagen gene have been reported in different families with EDS IV. Recent results support the hypothesis that in EDS IV, dominant inheritance should be assumed, in sporadic cases also, unless proven otherwise. Very little is known about the genetics or biochemicals defects responsible for the others EDS subtypes, but with the applications of the tools of molecular biology, analysis of these defects if now within reach.
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PMID:[Ehlers-Danlos syndromes. Clinical, genetic and molecular aspects]. 852 13

Three copper-resistant variants of cultured Chinese hamster ovary (CHO) cells were isolated and each was shown to accumulate less intracellular copper than the parental cells when grown in copper-supplemented media. The reduced copper accumulation was related to enhanced copper efflux. As cultured cells from patients with Menkes disease (mutations in MNK; ATP7A gene) accumulate copper, probably due to defective copper efflux, we investigated the possible role of the MNK gene in the molecular basis of copper resistance. We found increased MNK mRNA and MNK protein in all three resistant variants. The MNK protein, which has not been previously demonstrated experimentally in mammalian cells, was observed to have an apparent molecular weight of 178 kDa on SDS gels. The degree of increase in MNK mRNA and protein correlated well with the level of copper resistance and extent of copper efflux. By Southern blot and FISH analysis we determined that the molecular basis for overexpression of MNK was genomic amplification of the MNK gene. These data, combined with the clinical and cellular phenotype in Menkes disease, provide strong evidence that the MNK protein is involved in transmembrane copper efflux, and demonstrate a new system of gene amplification in mammalian cells.
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PMID:Gene amplification of the Menkes (MNK; ATP7A) P-type ATPase gene of CHO cells is associated with copper resistance and enhanced copper efflux. 858 89

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

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

The mouse homologue of the Menkes gene has been shown to span 120 kb of genomic DNA and to be similar in structure to both its human MNK homologue (ATP7A) and the Wilson disease gene (WD; ATP7B). Conservation of the majority of intron/exon boundaries among the three genes was also observed. The high overall conservation of both the Atp7a gene and the direction of transcription of the Atp7a, Pgk1, and Xnp genes between human and mouse is compatible with the evolution of an ancestral gene subject to strong evolutionary constraints lying within a locally relatively conserved region of the X chromosome.
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PMID:Genomic organization of the mottled gene, the mouse homologue of the human Menkes disease gene. 892 75

We have generated polyclonal antibodies against the amino-terminal third of the Menkes protein (ATP7A; MNK) by immunizing rabbits with a histidine-tagged MNK fusion construct containing metal-binding domains 1-4. The purified antibodies were used in Western analysis of cell lysates and in indirect immunofluorescence experiments on cultured cells. On Western blots, the antibodies recognized the approximately 165 kDa MNK protein in CHO cells and human fibroblasts. No MNK signal could be detected in fibroblasts from a patient with Menkes disease or in Hep3B hepatocellular carcinoma cells, confirming the specificity of the antibodies. Immunocytochemical analysis of CHO cells and human fibroblasts showed a distinct perinuclear signal corresponding to the pattern of the Golgi complex. This staining pattern was similar to that of alpha-mannosidase II which is a known resident enzyme of the Golgi complex. Using brefeldin A, a fungal inhibitor of protein secretion, we further demonstrated that the MNK protein is localized to the trans-Golgi network. This data provides direct evidence for a subcellular localization of the MNK protein which is similar to the proposed vacuolar localization of Ccc2p, the yeast homolog of MNK and WND (ATP7B), the Wilson disease gene product. In light of the proposed role of MNK both in subcellular copper trafficking and in copper efflux, these data suggest a model for how these two processes are linked and represent an important step in the functional analysis of the MNK protein.
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PMID:Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network. 914 44

Mutations in the Atp7a gene, the mouse homologue of the MNK (ATP7A) gene, have been suggested to be responsible for the mottled phenotype. To date, despite considerable effort, changes associated with the mottled mutations have been detected in only two such mutants. In this study, we identify changes in the level of Atp7a transcript and mutations which could explain the mottled phenotype in nine out of the 10 mutants analysed. The fluorescence-assisted mismatch analysis method used here has proved particularly well suited for mRNA scanning of heterozygous carrier animals, because of its ability to detect mutations even in the presence of an excess of wild-type mRNA. The three new underlying mutations identified at the Atp7a locus include a splice mutation and two missense mutations. While the spectrum of mutations detected in the Atp7a murine gene provides an explanation for at least part of the wide phenotypic variation observed in mottled mutant mice, there is a singular absence of deletions which are associated with a sizeable fraction of human Menkes syndrome cases.
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PMID:The mottled mouse as a model for human Menkes disease: identification of mutations in the Atp7a gene. 915 60

The brindled mouse mutant (Mo(br)) is the closest animal model of the human genetic copper deficiency, Menkes disease, which is presumed to be due to a mutation at the X-linked mottled locus (Mo). The mutant mice are hypopigmented and die at around 15 days after birth, but can be saved by treatment with copper before the 10th postnatal day. Menkes disease has been shown to be due to mutations of the gene ATP7A which encodes P-type ATPase (referred to here as MNK). MNK is likely to function in copper efflux from cells, but the full range of its biological activity is not fully understood. The nature of the mutation in the brindled mouse is of importance in our understanding of the role of MNK and for devising treatment strategies for Menkes disease. Here we show that the brindled mouse has a deletion of two amino acids in a highly conserved, but functionally uncharacterized, region of Mnk. Comparison with the Ca ATPases suggests this region may be involved in conformational changes associated with the E1/E2 transition fundamental to the action of P-type ATPases. We also describe the first Western blot data for Mnk in tissues, and these show normal levels of Mnk in mutant and brindled kidneys but none in liver. In the kidney, immunohistochemistry demonstrated Mnk in the proximal and distal tubules, the distribution is identical in mutant and normal. This distribution is consistent with Mnk being involved in copper resorption from the urine.
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PMID:Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease. 921 72

N-terminal domains of the Wilson's and Menkes disease proteins (N-WND and N-MNK) were overexpressed in a soluble form in Escherichia coli as fusions with maltose-binding protein, purified, and their metal-binding properties were characterized. Both N-MNK and N-WND bind copper specifically as indicated by the results of metal-chelate chromatography, direct copper-binding measurements, and chemical modification of Cys residues in the presence of different heavy metals. When E. coli cells are grown in the presence of copper, N-MNK and N-WND bind copper in vivo with stoichiometry of 5-6 nmol of copper/nmol of protein. Copper released from the copper-N-MNK and copper-N-WND complexes reacts with the Cu(I)-selective chelator bicinchoninic acid in the absence of reducing agents. This suggests that in proteins, it is bound in reduced Cu(I) form, in agreement with the spectroscopic properties of the copper-bound domains. Copper bound to the domains in vivo or in vitro specifically protects the N-MNK and N-WND against labeling with the cysteine-directed probe; this indicates that Cys residues in the repetitive motifs GMTCXXCXXXIE are involved in coordination of copper. Direct involvement of the N-terminal domains in the binding of copper suggests their important role in copper-dependent functions of human copper-transporting adenosine triphosphatases (Wilson's and Menkes disease proteins).
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PMID:N-terminal domains of human copper-transporting adenosine triphosphatases (the Wilson's and Menkes disease proteins) bind copper selectively in vivo and in vitro with stoichiometry of one copper per metal-binding repeat. 922 74

The Menkes ATPase is the product of the MNK gene, defective in some inherited human disorders of copper metabolism. We here show the formation of an acylphosphate intermediate by the murine MNK homologue in membranes from normal and copper resistant Chinese hamster ovary cells. In the latter, fivefold higher levels of acylphosphate were formed. Challenging these cells with copper, which induces relocation of the MNK ATPase from the trans-Golgi network to the plasma membrane, did not influence acylphosphate formation. The kinetics of phosphorylation, metal dependence, and sensitivity to inhibitors were investigated. The results show that the MNK ATPase is an active P-type ATPase and provide a direct functional test for this enzyme.
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PMID:Acylphosphate formation by the Menkes copper ATPase. 925 13


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