Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A candidate gene (ATP7B) for Wilson's disease, an autosomal recessive disorder of copper transport, has recently been identified. We examined the ATP7B gene in two Japanese sisters with Wilson's disease presenting with fulminant hepatic failure but who did not exhibit Kayser-Fleischer rings or abnormal neurological findings. Genomic DNA was isolated from the whole blood of the patients and their family. Entire exons of ATP7B, and their associated splice junctions, were amplified by polymerase chain reaction. The sequencing of all exons was performed by a non-radioactive sequencing method. The sequencing of exon 12 of ATP7B revealed a 9-bp deletion. The mutation deleted 922Gly, 923Tyr, and 924Phe, and three residues conserved in the Menkes gene, ATP7A, located in the fifth transmembrane region. Of the 14 family members tested, 7 were normal and 7 were heterozygous for the deletion. Mean serum copper and cerulopasmin levels were significantly lower in the family members who were heterozygous for the deletion than in the normal family members, and two heterozygous family members showed abnormally low ceruloplasmin levels; however, there were no differences in mean aspartate aminotransferase or alanine aminotransferase levels between the two groups.
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PMID:A new variant deletion of a copper-transporting P-type ATPase gene found in patients with Wilson's disease presenting with fulminant hepatic failure. 1077 57

A recent study reported an increase of brain tissue copper content in the lentiform nuclei of patients with primary adult-onset dystonia. In this study we analyze copper-metabolizing proteins (Menkes protein, Wilson protein, ceruloplasmin) by Western blot analysis in frozen brain tissue (lentiform nuclei) of 3 patients with primary dystonia. Menkes protein was reduced in all patients, while Wilson protein and ceruloplasmin were increased in the 2 patients with focal dystonia and reduced in the patient with generalized dystonia. Our data provides further evidence for a disturbance of copper metabolism in primary dystonia.
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PMID:Changes of copper-transporting proteins and ceruloplasmin in the lentiform nuclei in primary adult-onset dystonia. 1085 53

The interaction was studied of ceruloplasmin (Cp, EC 1.16.3.1), a copper-containing plasma protein, with two synthetic peptides P15 and P16 whose structures correlate with those of the noncytosolic regions of the copper transfer P1 type ATPase (ATP7A), apparently encoded by the Menkes disease gene (Atp7a). Pentadecapeptide P15 and hexadecapeptide P16 were synthesized using the solid phase method. They correspond to fragments of two extracellular loops ATP7A, of which one loop is apparently involved in the copper ion transfer (P16) whereas the other is not (P15). The protein footprinting showed that P16 binds to a fragment of the ceruloplasmin domain 6. Kinetics of the ceruloplasmin-P16 binding was studied by affinity chromatography on P16 immobilized on a macroporous disk, and the Kd value (1.5 x 10(-6) M) of this interaction was determined. The ATP7A involvement in the copper ion transfer to nonhepatocyte cells is discussed.
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PMID:[Identification of a fragment of ceruloplasmin, interacting with copper-transporting Menkes ATPase]. 1104 Sep 94

Copper (Cu) is an essential trace element and constitutes the active center of the redox Cu enzymes such as Cu, Zn-superoxide dismutase (Cu, Zn-SOD), ceruloplasmin and cytochrome c oxidase. Among hereditary diseases due to a defect in the metabolism of Cu, Menkes disease (caused by a Cu deficiency) and Wilson disease (caused by the excessive accumulation of Cu) have been shown to be caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu, ATP7A and ATP7B, respectively. Following the identification of these causative genes, intracellular Cu transporters (Cu chaperones) specific for the Golgi apparatus, mitochondria and Cu, Zn-SOD were discovered, and these findings have facilitated the study of the underlying mechanisms of the biological regulation of Cu. Apart from these physiological and biochemical studies, toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. In these toxicological studies, two biological aspects of metallothionein (MT), i.e., antioxidant and prooxidant depending on the Cu/Zn ratio in Cu-containing MT have been proposed. The present article overviews the recent findings on the biological regulation of Cu and on the toxicological aspect of Cu. It is known that Cu forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. On the basis of this observation, tetrathiomolybdate (TTM) has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC) rats. Precise mechanisms underlying the complex formation between Cu bound to MT and TTM were presented, and an appropriate protocol for the chelation therapy was also proposed together with the mechanisms underlying the occurrence of side-effects.
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PMID:[Biological regulation of copper and selective removal of copper: therapy for Wilson disease and its molecular mechanism]. 1108 2

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

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


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