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 trace metal copper (Cu) plays an essential role in biology as a cofactor for many enzymes that include Cu, Zn superoxide dismutase, cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine beta-hydroxylase. Consequently, Cu transport at the cell surface and the delivery of Cu to intracellular compartments are critical events for a wide variety of biological processes. The components that orchestrate intracellular Cu trafficking and their roles in Cu homeostasis have been elucidated by the studies of model microorganisms and by the characterizations of molecular basis of Cu-related genetic diseases, including Menkes disease and Wilson disease. However, little is known about the mechanisms for Cu uptake at the plasma membrane and the consequences of defects in this process in mammals. Here, we show that the mouse Ctr1 gene encodes a component of the Cu transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation. These results demonstrate a crucial role for Cu acquisition through the Ctr1 transporter for mammalian Cu homeostasis and embryonic development.
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PMID:Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. 1139 Oct 5

Using the immunoblotting method, the synthesis of two copper-transporting P1-type ATPases, ATP7A (a candidate for the product of the Menkes disease gene) and ATP7B (presumed product of the Wilson disease gene), in the yolk sac cells of rat embryos at days 11 and 20 of embryogenesis was demonstrated. Concomitantly, yolk sac cells produce ceruloplasmin, a soluble copper-transporting glycoprotein, a proportion of which in secreted proteins progressively diminishes, attaining 5.2% at day 11 and 3.1% at day 20 of development. At different stages of embryogenesis, yolk sac cells synthesize two molecular forms of [14]C-ceruloplasmin, one of which is secreted towards the embryo, whereas the other, towards the decidual membrane. Two forms of ceruloplasmin secreted in polar directions differ in the rate of secretion. The role of the yolk sac as a key organ controlling the delivery and secretion of copper in the embryo during the postimplantation period is discussed.
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PMID:[The role of the yolk sac in copper metabolism during rat embryogenesis]. 1154 10

A few patients with an affected CNS involving abnormalities in copper metabolism have been described that do not fit any known nosological entities such as Wilson's disease or Menkes' disease. Three sporadic patients (two men and one woman) were examined with involuntary movements and dysarthria associated with abnormal concentrations of serum copper, serum ceruloplasmin, and urinary copper excretion. The onset of neurological symptoms occurred at the age of 15 to 17 years. The common clinical symptoms were involuntary movements and dysarthria. The involuntary movements included dystonia in the neck, myoclonus in the shoulder, athetosis in the neck, and rapid orobuccal movements. The dysarthria consisted of unclear, slow, and stuttering speech. Two of the three patients did not have dementia. A cousin of the female patient had been diagnosed as having Wilson's disease and had died of liver cirrhosis. Laboratory findings showed a mild reduction in serum copper and ceruloplasmin concentrations, whereas urinary copper excretion was significantly reduced in all three patients. Two of the three patients showed a high signal intensity in the basal ganglia on T2 weighted brain MRI. In conclusion, the unique findings of involuntary movements, dysarthria, and abnormal serum copper and urinary copper concentrations suggest that the three patients may constitute a new clinical entity that is distinct from either Wilson's or Menkes disease.
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PMID:A new neurological entity manifesting as involuntary movements and dysarthria with possible abnormal copper metabolism. 1172 1

Iron and copper are essential transition metals that permit the facile transfer of electrons in a series of critical biochemical pathways. Recent work has identified the specific proteins involved in the absorption, transport, utilization, and storage of iron and copper. Remarkable progress is being made in understanding the molecular basis of disorders of human iron and copper metabolism. This review describes these proteins and examines the clinical consequences of new insights into the pathophysiology of genetic abnormalities affecting iron and copper metabolisms. Hereditary hemochromatosis is the most common genetic disorder of iron metabolism caused by mutations in the HFE gene. Aceruloplasminemia is a rare iron metabolic disorder that results from deficiency of ceruloplasmin ferroxidase activity as a consequence of mutations in the ceruloplasmin gene. Menkes disease and Wilson's disease are inherited disorders of copper metabolism resulting from the absence or dysfunction of homologous copper-transporting ATPases.
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PMID:Genetic disorders affecting proteins of iron and copper metabolism: clinical implications. 1241 92

Copper transporting P-type ATPases, designated ATP7A and ATP7B, play an essential role in mammalian copper balance. Impaired intestinal transport of copper, resulting from mutations in the ATP7A gene, lead to Menkes disease in humans. Defects in a similar gene, the copper transporting ATPase ATP7B, result in Wilson disease. This ATP7B transporter has two functions: transport of copper into the plasma protein ceruloplasmin, and elimination of copper through the bile. Variants of ATP7B can be functionally assayed to identify defects in each of these functions. Tissue expression studies of the copper ATPases and their copper chaperone ATOX1 indicate that there is not complete overlap in expression. Other chaperones may be important for the transport of copper into ATP7A and ATP7B.
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PMID:Copper transporting P-type ATPases and human disease. 1253 60

The human copper chaperone HAH1 transports copper to the Menkes and Wilson proteins, which are copper-translocating P-type ATPases located in the trans-Golgi apparatus and believed to provide copper for important enzymes such as ceruloplasmin, tyrosinase, and peptidylglycine monooxygenase. Although a substantial amount of structural data exist for HAH1 and its yeast and bacterial homologues, details of the copper coordination remain unclear and suggest the presence of two protein-derived cysteine ligands and a third exogenous thiol ligand. Here we report the preparation and reconstitution of HAH1 with Cu(I) using a protocol that minimizes the use of thiol reagents believed to be the source of the third ligand. We show by x-ray absorption spectroscopy that this reconstitution protocol generates an occupied Cu(I) binding site with linear biscysteinate coordination geometry, as evidenced by (i) an intense edge absorption centered at 8982.5 eV, with energy and intensity identical to the rigorously linear two-coordinate model complex bis-2,3,5,6-tetramethylbenzene thiolate Cu(I) and (ii) an EXAFS spectrum that could be fit to two Cu-S interactions at 2.16 A, a distance typical of digonal Cu(I) coordination. Binding of exogenous ligands (GSH, dithiothreitol, and tris-(2-carboxyethyl)-phosphine) to the Cu(I) was investigated. When GSH or dithiothreitol was added to the chaperone during the reconstitution procedure, the resulting Cu(I)- HAH1 remained two-coordinate, whereas the addition of the phosphine during reconstitution elicited a three-coordinate species. When the exogenous ligands were titrated into the Cu(I)-HAH1, all formed three-coordinate adducts but with differing affinities. Thus, GSH and dithiothreitol showed weaker binding, with estimated KD values in the range 10-25 mm, whereas tris-(2-carboxyethyl)-phosphine showed stronger affinity, with a KD value of <5 mm. The implications of these findings for mechanisms of copper transport are discussed.
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PMID:X-ray absorption spectroscopy of the copper chaperone HAH1 reveals a linear two-coordinate Cu(I) center capable of adduct formation with exogenous thiols and phosphines. 1268 48

Copper is essential for brain metabolism, serving as a cofactor to superoxide dismutase, dopamine-beta-hydroxylase, amyloid precursor protein, ceruloplasmin, and other proteins required for normal brain function. The copper-transporting ATPases ATP7A and ATP7B play a central role in distribution of copper in the central nervous system; genetic mutations in ATP7A and ATP7B lead to severe neurodegenerative disorders, Menkes disease and Wilson disease, respectively. Although both ATP7A and ATP7B are required, their specific roles and regulation in the brain remain poorly understood. Using high-resolution imaging and functional assays, we demonstrate that ATP7A and ATP7B show cell-specific distribution in adult cerebellum, have distinct enzymatic characteristics, and are regulated differently during development. ATP7B is continuously expressed in Purkinje neurons (PN) where it delivers copper to the ferroxidase ceruloplasmin. ATP7A is a faster copper transporter than Wilson disease protein as evidenced by faster rates of catalytic reactions. The expression of ATP7A switches during development from PN to Bergmann glia, the cells supporting PN function in adult brain. Inactivation of ATP7B (Wilson disease protein) by gene knock-out induces a striking shift in the expression of the ATP7B target protein, ceruloplasmin, from PN to Bergmann glia, where ATP7A (Menkes disease protein) is present. The induced cell-specific change in expression restores copper delivery to ceruloplasmin via ATP7A. Overall, the results provide evidence for distinct functions of ATP7A and ATP7B in the cerebellum and illustrate a tight link between copper homeostasis in PN and Bergmann glia.
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PMID:The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. 1563 71

Wilson's disease and Menkes disease are inherited genetic disorders of copper metabolism. Each disease results from the absence or dysfunction of homologous copper-transporting ATPases present in the trans-Golgi network of cells. The Wilson ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, patients with Wilson's disease of the autosomal recessive trait present with signs and symptoms arising from impaired biliary copper excretion. The Menkes ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The different clinical features of each disease are the results of the tissue specific expression of these ATPases. In Wilson's disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected patients usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a results of copper accumulation in the basal ganglia and other brain regions. The diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the genes of patients with Wilson disease. Copper chelation drugs and zinc are effective in most cases. New treatment guidelines now advise physicians to start patients on zinc.
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PMID:[Genetic disorders of copper transport--diagnosis and new treatment for the patients of Wilson's disease]. 1577 21

Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.
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PMID:Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism. 1590 51

Menkes syndrome is caused by mutation of ATP7A gene that encode copper-binding membrane protein localized to the trans-Golgi membrane. Mutation of this gene causes defective exportation of copper from the cell. Intracellular accumulation of copper does not reach the toxic state, as copper entering the body is trapped in the intestinal epithelium. Copper requiring enzymes are dysfunction and cause multisystemic manifestations. The authors report a Thai boy 8 months of age who had depigmentation and kinky hair at birth. He developed myoclonic jerk at 3 months of age. He had hypopigmentation of the skin, delayed development, hypotonia, pectus excurvatum, loose skin and joints. He had anemia, very low serum copper and ceruloplasmin. X-ray showed Wormian bone of skull, osteopenia of long bones and generalized brain atrophy. The presented case has similar clinical and laboratory findings to 2 previous reports by Songkla University and Siriraj Hospital. Treatment is not effective due to unavailability of copper- histidinate and the patient already had severe brain damage. Genetic counseling is important to prevent the next offspring. Biochemical and molecular diagnosis are available for confirmation and prenatal diagnosis, but these techniques have limitations in Thailand.
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PMID:Menkes syndrome: a case report. 1685 71


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