Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most cases of early onset torsion dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on human chromosome 9q34. Both genes comprise five similar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junctions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N = 17), in dystonic individuals with apparent homozygosity in the 9q34 chromosomal region (N = 5), or in a representative Ashkenazic Jewish individual with late onset dystonia, who shared a common haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50-70% similarity) and their orthologues in species including human, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human genome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch.
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PMID:The TOR1A (DYT1) gene family and its role in early onset torsion dystonia. 1064 35

Wilson's disease is an autosomal recessive disorder of copper metabolism resulting from the absence or dysfunction of a copper transporting P-type ATPase encoded on chromosome 13. This ATPase is expressed in hepatocytes where it is localized to the trans-Golgi network and transports copper into the secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Under physiologic circumstances, biliary excretion represents the sole mechanism for copper excretion, and thus affected individuals have progressive copper accumulation in the liver. When the capacity for hepatic storage is exceeded, cell death ensues with copper release into the plasma, hemolysis, and tissue deposition. Presentation in childhood may include chronic hepatitis, asymptomatic cirrhosis, or acute liver failure. In young adults, neuropsychiatric symptoms predominate and include dystonia, tremor, personality changes, and cognitive impairments secondary to copper accumulation in the central nervous system. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 100 unique mutations have been identified and most individuals are compound heterozygotes. Copper chelation with penicillamine is an effective therapy in most patients and hepatic transplantation is curative in individuals presenting with irreversible liver failure. Elucidation of the molecular genetic basis of Wilson's disease has permitted new insights into the mechanisms of cellular copper homeostasis.
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PMID:Wilson's disease. 1107 1

The pathogenesis of idiopathic adult onset dystonia (ID) is still unclear. Although neuropathologic studies did not reveal consistent abnormalities, electrophysiologic and neuroimaging findings point toward a disinhibition and overactivity of the frontal motor cortical areas caused by an altered basal ganglia outflow. The lentiform nuclei are assumed to play a major role in this scenario. Recent neurochemical analysis of brain tissue stimulated by transcranial ultrasound studies demonstrated an increased copper content of the lentiform nuclei in patients with ID. The shift of brain copper level may substantially influence neuronal activity causing a reduced inhibitory output from the lentiform nuclei to the motor cortex. The reason for the presumably altered copper metabolism is not clear, but preliminary findings suggest that reduced levels of the Menkes protein, a membrane ATPase exporting copper out of the cells, may be implicated. Disturbances of brain copper metabolism may explain various phenomena of ID; however, it needs to be determined whether these observations represent the basic pathogenetic mechanism of ID or reflect another as yet unidentified pathologic process.
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PMID:Evidence for disturbances of copper metabolism in dystonia: from the image towards a new concept. 1175 12

Early-onset torsion dystonia is an autosomal dominant movement disorder that has been linked to the deletion of one of a pair of glutamic acid residues in the protein torsinA (E(302/303); DeltaE-torsinA). In transfected cells, DeltaE-torsinA exhibits similar biochemical properties to wild type (WT)-torsinA, but displays a distinct subcellular localization. Primary structural analysis of torsinA suggests that this protein is a membrane-associated member of the AAA family of ATP-binding proteins. However, to date, neither WT- nor DeltaE-torsinA has been obtained in sufficient quantity and purity to permit detailed biochemical and biophysical characterization. Here, we report a baculovirus expression system that provides milligram quantities of purified torsin proteins. Recombinant WT- and DeltaE-torsinA were found to be membrane-associated glycoproteins that required detergents for solubilization and purification. Analysis of the biophysical properties of WT- and DeltaE-torsinA indicated that both proteins were folded monomers in solution that exhibited equivalent denaturation behaviors under thermal and chaotropic (guanidinium chloride) stress. Additionally, both forms of torsinA were found to display ATPase activity with similar k(cat) and K(m) values. Collectively, these data reveal that torsinA is a membrane-associated ATPase and indicate that the DeltaE(302/303) dystonia-associated mutation in this protein does not cause gross changes in its catalytic or structural properties. These findings are consistent with a disease mechanism in which DeltaE-torsinA promotes dystonia through a gain rather than loss of function. The recombinant expression system for torsinA proteins described herein should facilitate further biochemical and structural investigations to test this hypothesis.
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PMID:Recombinant expression, purification, and comparative characterization of torsinA and its torsion dystonia-associated variant Delta E-torsinA. 1469 Apr 43

Early-onset torsion dystonia, a CNS-based movement disorder, is usually associated with a single amino acid deletion (Delta E302/303) in the protein torsinA. TorsinA is an AAA+ ATPase in the endoplasmic reticulum, but what it does is unknown. Here, we use torsinA mutants with defects in ATP hydrolysis (E171Q, ATP-bound) and ATP binding (K108A, ATP-free) to probe torsinA's normal cellular function. Surprisingly, ATP-bound torsinA is recruited to the nuclear envelope (NE) of transfected cells, where it alters connections between inner and outer nuclear membranes. In contrast, ATP-free torsinA is diffusely distributed throughout the endoplasmic reticulum and has no effect on the NE. Among AAA+ ATPases, affinity for substrates is high in the ATP-bound and low in the ATP-free state, leading us to propose that component(s) of the NE may be substrates for torsinA. We also find that the disease-promoting Delta E302/303 mutant is in the NE, and that this relocalization, as well as the mutant's previously described ability to induce membranous inclusions, is eliminated by the K108A ATP-binding mutation. These results suggest that changes in interactions involving torsinA in the NE could be important for the pathogenesis of dystonia and point to torsinA and related proteins as a class of ATPases that may operate in the NE.
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PMID:TorsinA in the nuclear envelope. 1518 29

Early onset generalized dystonia is a severe form of primary dystonia linked to a mutation of the DYT1(TOR1A) gene on chromosome 9q34. DYT1 gene codifies for human torsinA, an AAA+ ATPase associated with the membranes of endoplasmic reticulum (ER) and the synaptic vesicles and proposed to be involved in trafficking of tubular-vesicular membrane through neuronal processes. In this study, the presence and the intracellular distribution of torsinA protein in SH-SY5Y neuroblastoma cells were evaluated by immunofluorescence and Western blot analysis following differentiation with retinoic acid and BDNF. Protein expression was then inhibited by transient antisense transfection and the possible effect on neurite outgrowth was observed. In SH-SY5Y cells torsinA, with an apparent MW of 38 kDa, is endogenously present and distributed, with a punctate pattern, in the cytosol and along the neurites. The protein showed high intensity of immunoreactivity in the neurite varicosities and was partially co-localized with vesicles markers. Terminally differentiated cells showed an increase of protein expression. Oligonucleotide antisense treatment induced a significant response to differentiating stimuli, lead to sprouting of longer neurites and increase in growth cone areas. A relationship between torsinA and tau protein, which is involved in axon elongation and establishment of neuronal polarity, was demonstrated by co-immunoprecipitation experiments. These findings suggest that torsinA, throughout the interaction with microtubule associated proteins, may contribute to control neurite outgrowth and could be involved in maintaining cell polarity.
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PMID:TorsinA negatively controls neurite outgrowth of SH-SY5Y human neuronal cell line. 1515 63

Dystonia is a disorder of involuntary sustained muscle contraction, which usually affects a focal region of the body but may be generalized and results in twisting contorted movements or abnormal postures. Several clinical subtypes of dystonia have been delineated and many have a strong inherited basis. In this issue of Neuron, de Carvalho Aguiar and colleagues report the identification of missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) as a cause of rapid-onset dystonia-parkinsonism (RDP, DYT12).
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PMID:Paying the price at the pump: dystonia from mutations in a Na+/K+ -ATPase. 1526 Sep 53

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.
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PMID:Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. 1526 Sep 48

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

Early-onset dystonia is caused by mutations in the torsinA protein, a putative member of the AAA+ class of ATPases. In this study we have evaluated the ATPase activity of bacterially expressed wild-type torsinA and its disease-associated mutant forms. Upon overexpression in Escherichia coli, recombinant torsinA proteins were accumulated as insoluble inclusion bodies and required refolding to become soluble and catalytically active. The refolded wild-type and mutant torsinA proteins were capable of hydrolyzing ATP, but their specific ATPase activities differed significantly. Deletions of the amino acid residues E302/303 and F323-Y328 resulted in a decrease of ATPase activity to approximately 35% and approximately 75% of the wild-type level, respectively. ATPase activity of wild-type and mutant torsinA proteins was influenced by factors that varied with cell stress, such as temperature, pH, and ionic strength, and was inhibited by sodium vanadate. Our results provide the first direct evidence for a role of torsinA as an active ATPase and suggest that the mutations in torsinA might affect normal functions of the protein by reducing its enzymatic activity.
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PMID:Dystonia-associated forms of torsinA are deficient in ATPase activity. 1578 71


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