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)

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

Menkes disease is a fatal neurodegenerative disorder of childhood caused by the absence or dysfunction of a putative P-type ATPase encoded on the X chromosome. To elucidate the function of the Menkes disease protein, a plasmid containing the open reading frame of the human Menkes disease gene was constructed and used to transform a strain of Saccharomyces cerevisiae deficient in CCC2, the yeast Menkes/Wilson disease gene homologue. ccc2Delta yeast are deficient in copper transport into the secretory pathway, and expression of a wild type human Menkes cDNA complemented this defect, as evidenced by the restoration of copper incorporation into the multicopper oxidase Fet3p. Site-directed mutagenesis demonstrated the essential role of four specific amino acids in this process, including a conserved histidine, which is the site of the most common disease mutation in the homologous Wilson disease protein. The expression of Menkes cDNAs with successive mutations of the conserved cysteine residues in the six amino-terminal MXCXXC metal binding domains confirmed the essential role of these cysteine residues in copper transport but revealed that each of these domains is not functionally equivalent. These data demonstrate that the Menkes disease protein functions to deliver copper into the secretory pathway of the cell and that this process involves biochemical mechanisms common to previously characterized members of this P-type ATPase family.
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PMID:Functional expression of the menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases. 945 9

We report on the long-term clinical course of 4 boys with Menkes disease, treated from early infancy with parenteral copper-histidine, with follow-up over 10-20 years. Three of the 4 had male relatives with a severe clinical course compatible with classical Menkes disease. As a consequence of early treatment, our patients have normal or near-normal intellectual development, but have developed many of the more severe somatic abnormalities of the related disorder, occipital horn syndrome, including severe orthostatic hypotension in 2. In addition, 1 boy developed a previously unreported anomaly, namely, massive splenomegaly and hypersplenism as a consequence of a splenic artery aneurysm. Previously reported molecular studies in 2 of these patients had shown gene defects which would have predicted a truncated and probably nonfunctional gene product. Despite the favorable effects on the neurological symptoms, parenteral copper treatment for Menkes disease should still be regarded as experimental. The development of more effective treatments must await a more precise delineation of the role which the Menkes protein plays in intracellular copper trafficking.
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PMID:Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients. 951 79

In the 25 y since copper deficiency was first delineated in persons with Menkes syndrome, advances in our understanding of the clinical, biochemical, and molecular aspects of this rare disorder have surpassed progress in the design of effective therapies. In contrast with purely nutritional copper deficiency, in which copper replacement can be curative, the nature of the basic defect in Menkes syndrome suggests that corrective efforts are likely to be more complicated, a point supported by the cumulative literature on this topic as well as by emerging molecular data. In this paper, certain clinical, biochemical, and molecular aspects of copper histidine treatment in 25 Menkes syndrome patients at the National Institutes of Health are reviewed. The delineation of a distinctive neurochemical pattern in plasma and cerebrospinal fluid, reflecting deficiency of the copper enzyme dopamine beta-monooxygenase, is arguably the most important finding in the study of Menkes syndrome. This abnormal pattern has proven extremely reliable as a rapid diagnostic test, enabling early identification of affected infants--a fundamental requirement for improving clinical outcomes. Of 11 patients identified by prenatal or prompt postnatal testing and treated within the first 10 d of age, one walked at 14 mo of age and has normal neurodevelopment at age 3 y and another infant's early progress appears promising. However, five patients died in infancy and neurodevelopmental outcome was suboptimal in four others. Consideration of additional therapeutic strategies seems necessary, therefore, for most patients and families facing this troublesome form of copper deficiency.
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PMID:Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. 958 47

We report the rare presentation of Menkes disease with a congenital skull fracture, intracerebral bleeding, and seizures. The diagnosis was made at 3 months of age based on the characteristic features of the syndrome, by which time the child experienced uncontrollable seizures. Following progressive neurodegeneration, death occurred at 3 years of age. The prognosis in Menkes disease is dependent on early copper-histidine therapy. Effective treatment has led to children surviving into adulthood. Diagnosing the syndrome during the neonatal period is difficult. There are no published reports of congenital skull fracture as a presenting sign of Menkes disease. It is concluded that Menkes disease should be considered in any child who presents with congenital skull fracture as early diagnosis and treatment significantly improve the outcome.
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PMID:Congenital skull fracture as a presentation of Menkes disease. 1085 57

The Enterococcus hirae ATPase CopA is a member of the recently discovered heavy metal ATPases and shares 43% sequence identity with the human Menkes and Wilson copper ATPases. To study CopA biochemically, it was overexpressed in E. coli with an N-terminal histidine tag and purified to homogeneity by nickel affinity chromatography. The purified CopA catalyzed ATP hydrolysis with a V(max) of 0.15 micromol/min/mg and a K(m) for ATP of 0.2 mM and had an optimum pH of 6.25. The activity was 3- to 4-fold stimulated by reconstitution into proteoliposomes. The enzyme formed an acylphosphate intermediate. Its kinetics of formation and the effects of inhibitors and metal ions upon it support a function of CopA in copper transport. Purification and functional reconstitution of CopA provides the basis to study copper transport in vitro.
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PMID:Purification and functional analysis of the copper ATPase CopA of Enterococcus hirae. 1116 79

Epileptic seizures are a common feature in Menkes disease, an X-linked genetic disorder of copper metabolism. Details of type of seizures are rarely reported. We report the evolution of infantile spasms in two patients with Menkes disease and the relation with subcutaneous administration of copper-histidine.
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PMID:Infantile spasms and Menkes disease. 1117 54

Genomic DNA of 17 unrelated Japanese males with Menkes disease and 2 Japanese males with occipital horn syndrome were studied for mutations in the ATP7A gene. Using SSCP analysis and direct sequencing of the exons and the 5'-upstream region of the gene amplified by PCR, we identified 16 mutations in 16 of 17 males with Menkes disease, including 4 deletions, 2 insertions, 6 nonsense mutations, 2 missense mutations, and 2 splice-site mutations. All these mutations were those that affect the function of the gene. Of the two males with occipital horn syndrome, one had a splice-site mutation in intron 6 that led to normal-size and smaller-size transcripts. The amount of the normal-size transcripts in his cultured skin fibroblasts was 19% of the normal level. His serum copper and ceruloplasmin levels were normal, whereas his cultured skin fibroblasts contained increased levels of copper. These findings indicate that his mild clinical manifestations were due to the presence of normal-size and presumably functional transcripts of the gene. DNA sequencing analysis of the exons and 5'-upstream region of the ATP7A gene in 20 normal individuals and the 19 affected males identified 25 polymorphisms.
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PMID:ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. 1124 93

Menkes disease (MD) is an X-linked recessive disorder of copper metabolism, characterized in its untreated state by progressive disorders of multiple systems, especially the central nervous system (CNS) and connective tissue, and death by 3 years of age. Recently, therapy with copper-histidine has modified the severity of MD and permitted survival into adolescence. Clinical response has been greater for the neurological abnormalities than for the connective tissue abnormalities. In this report, we describe the postmortem pathology of one individual who had received copper-histidine therapy and died at age 10; we believe this to be the first such pathological report. The postmortem examination demonstrated significant pathology of mesenchymal tissues, including skeletal abnormalities, vascular degeneration, and bladder diverticula. The CNS, by contrast, showed minimal pathology. The phenotype was more consistent with occipital horn syndrome, a milder allelic disorder of copper metabolism, than with classic MD. The differential sensitivity of CNS and mesenchymal tissues to copper-histidine therapy may result from heterogeneity in the response of different copper-dependent enzymes.
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PMID:Menkes disease after copper histidine replacement therapy: case report. 1137 Feb 66

The Enterococcus hirae CopB ATPase (EC 3.6.1.3) confers copper resistance to the organism by expelling excess copper. Two related human ATPase genes, ATP7A (EC 3.6.1.36) and ATP7B (EC 3.6.1.36), have been cloned as the loci of mutations causing Menkes and Wilson diseases, diseases of copper metabolism. Many mutations in these genes have been identified in patients. Since it has not yet been possible to purify the human copper ATPases, it has proved difficult to test the impact of mutations on ATPase function. Some mutations occur in highly conserved sequence motifs, suggesting that their effect on function can be tested with a homologous enzyme. Here, we used the E. hirae CopB ATPase to investigate the impact of such mutations on enzyme function in vivo and in vitro. The Menkes disease mutation of Cys-1000-->Arg, changing the conserved Cys-Pro-Cys ('CPC') motif, was mimicked in CopB. The corresponding Cys-396-->Ser CopB ATPase was unable to restore copper resistance in a CopB knock-out mutant in vivo. The purified mutant ATPase still formed an acylphosphate intermediate, but possessed no detectable ATP hydrolytic activity. The most frequent Wilson disease mutation, His-1069-->Gln, was introduced into CopB as His-480-->Gln (H480Q). This mutant CopB also failed to confer copper resistance to a CopB knock-out strain. Purified H480Q CopB formed an acylphosphate intermediate and retained a small, but significant, ATPase activity. Our results reveal that Cys-396 and His-480 of CopB are key residues for ATPase function, and similar roles are suggested for Cys-1000 and His-1069 of Menkes and Wilson ATPases respectively.
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PMID:Structure-function analysis of purified Enterococcus hirae CopB copper ATPase: effect of Menkes/Wilson disease mutation homologues. 1141 52


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