Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of the molecular defects in mouse mutants can identify candidate genes for human neurological disorders. During the past 2 years, mutations in sodium channels, calcium channels and potassium channels have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver. The phenotypes of four allelic mutations identified in the sodium channel gene Scn8a range from ataxia and muscle weakness through severe dystonia and progressive paralysis, indicating that human mutations in this gene could be associated with a variety of clinical syndromes. Mutations of the calcium channel subunits beta 4 in the lethargic mouse and alpha 1A in the tottering mouse have specific effects on cerebellar function. Targeted mutation of ligand-gated ion channels has also been used to generate new models of neurological disease. We will review these recent achievements and their implications for human neurological disease. The mouse studies indicate that mutations in ion channel genes are likely to be responsible for a broad spectrum of clinical phenotypes in human neurological disorders.
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PMID:Ion channel mutations in mouse models of inherited neurological disease. 956 26

We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the alpha 1A voltage-dependent P/Q-type Ca2+ channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified.
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PMID:Spinocerebellar ataxia type 6: MRI of three Japanese patients. 959 91

Neurotransmitter release, neuronal excitation, and a whole variety of other neuronal functions are controlled by the intra/extra cellular Ca2+ gradient. The major pathway for entry of Ca2+ into the excitable cells is mediated by voltage-gated Ca2+ channels. Several functional subclasses of voltage-dependent Ca2+ channels have been identified, based on their pharmacological, biophysical properties, and molecular cloning. Recently, three human diseases (familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia 6) were added to the growing list of ion-channel disorders, all caused by different mutations in the P/Q-type Ca2+ channel alpha 1 subunit. Molecular analysis of the Ca2+ channelopathies will provide new insights into the role, function and pathology of these voltage-gated Ca2+ channels.
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PMID:Genetics and pathology of voltage-gated Ca2+ channels. 969 Jan 39

Homozygous leaner mice carry an autosomal recessive mutation in the Ca2+ channel subunit gene, alpha1A, causing them to exhibit severe ataxia, petit-mal-like epilepsy and a myoclonus-like movement disorder. Expression of alpha1A mRNA in cerebella from 20-day-old homozygous leaner mice was compared to control mice, using in situ hybridization histochemistry. Expression of alpha1A protein was examined in cerebella from 20-day-old homozygous leaner and control mice using immunocytochemistry. No differences in either mRNA or protein expression of the alpha1A subunit were observed when homozygous leaner mice were compared to age-matched controls. Therefore, functional alterations in P/Q-Type Ca2+ channels containing the alpha1A subunit need to be explored to further understand the relationship of mutations in the alpha1A gene to the pathogenesis of the neurologic disorders occurring in leaner mice.
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PMID:Expression of calcium channel alpha1A mRNA and protein in the leaner mouse (tgla/tgla) cerebellum. 972 1

The leaner (tgla) mutation in mice results in severe ataxia and an overt neurodegeneration of the cerebellum. Positional cloning has revealed that the tgla mutation occurs in a gene encoding the voltage-activated calcium channel alpha1A subunit. The alpha1A subunit is highly expressed in the cerebellum and is thought to be the pore-forming subunit of P- and Q-type calcium channels. In this study we used both whole-cell and single-channel patch-clamp recordings to examine the functional consequences of the tgla mutation on P-type calcium currents. High-voltage-activated (HVA) calcium currents were recorded from acutely dissociated cerebellar Purkinje cells of homozygous leaner (tgla/tgla) and age-matched wild-type (+/+) mice. In whole cell recordings, we observed a marked reduction of peak current density in tgla/tgla Purkinje cells (-35.0 +/- 1.8 pA/pF) relative to that in +/+ (-103.1 +/- 5.9 pA/pF). The reduced whole-cell current in tgla/tgla cells was accompanied by little to no alteration in the voltage dependence of channel gating. In both genotypes, HVA currents were predominantly of the omega-agatoxin-IVA-sensitive P-type. Cell-attached patch-clamp recordings revealed no differences in single-channel conductance between the two genotypes and confirmed the presence of three distinct conductance levels (9, 13-14, and 17-18 pS) in cerebellar Purkinje cells. Analysis of patch open-probability (NPo) revealed a threefold reduction in the open-probability of channels in tgla/tgla patches (0.04 +/- 0.01) relative to that in +/+ (0.13 +/- 0.02), which may account for the reduced whole-cell current in tgla/tgla Purkinje cells. These results suggest that the tgla mutation can alter native P-type calcium channels at the single-channel level and that these alterations may contribute to the neuropathology of the leaner phenotype.
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PMID:Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. 974 39

Since a few years, many mutations in genes encoding voltage-dependent ion channels have been identified. The related disorders are quoted as "channelopathies". These mutations are responsible for several skeletal muscle, brain, heart or kidney diseases. Abnormal calcium channels genes are responsible for hypokaleamic periodic paralysis (CACNA1S) as well as some forms of ataxia, cerebellar degeneration and migraine (CACNA1A). The preliminary studies of the recently discovered calcium channelopathies are undergoing. Both in vitro and in vivo studies of the diseased genes should help to the understanding of the related pathologies as well as to extend our knowledge of calcium channel function. In addition, autoantibodies against calcium channels are retrieved in some autoimmune diseases, such as Lambert-Eaton myasthenic syndrome (LEMS). Complementary studies are necessary to identify the precise implication of calcium channels in these auto-immune channelopathies.
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PMID:[Physiopathology of calcium channels: identification of calcium channelopathies]. 975 59

Diisopropyl phosphorofluoridate (DFP) produces organophosphorus ester-induced delayed neurotoxicity (OPIDN) in hen, human, and other sensitive species. A single dose of DFP (1.7 mg/kg, s.c.) produces mild ataxia in 7-14 days in hens, followed by progression to severe ataxia or paralysis. We studied the effect of DFP administration on Ca2+/calmodulin-dependent phosphorylation of tau proteins by the brain supernatants of control and DFP-treated hens. Brain supernatants from DFP-treated hens showed enhanced in vitro phosphorylation of htau40 and its various mutants, but no change in the two-dimensional phosphopeptide pattern, when compared to control hen brain supernatants. Analysis of tau mutants phosphorylated by brain supernatant and recombinant CaM kinase II alpha-subunit showed that (1) brain supernatant CaM kinase II is mainly responsible for the phosphorylation of Ser416, (2) Ser356, but probably not Ser262, is phosphorylated by CaM kinase II, (3) no amino acid between Lys395-Ala437 except Ser416 is phosphorylated by CaM kinase II, (4) a number of amino acids in the tau molecule, which are phosphorylated by the brain supernatant in the absence of Ca2+/calmodulin are also mildly phosphorylated by CaM kinase II. The enhanced Ca2+/calmodulin-dependent phosphorylation of tau proteins by brain supernatant of DFP-treated hens that includes phosphorylation of a number of amino acids is likely to alter the functional properties of tau proteins in OPIDN. The hyperphosphorylated tau may destabilize microtubules, alter axonal transport, and result in degeneration of axons in OPIDN.
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PMID:Tau proteins-enhanced Ca2+/calmodulin (CaM)-dependent phosphorylation by the brain supernatant of diisopropyl phosphorofluoridate (DFP)-treated hen: tau mutants indicate phosphorylation of more amino acids in tau by CaM kinase II. 982 62

A 5-year-old cow was evaluated because of a 2-week history of ataxia and other vague neurologic signs. Previous treatments included intravenous and orally administered calcium, but improvement was not seen. Bilateral mucoserous nasal discharge and a pair of firm, smooth masses caudodorsal to the eyes were found on the frontal bones on physical examination. The cow's condition deteriorated rapidly within 48 hours; head pressing and inability to rise were observed. The frontal sinuses were radiographically normal. Trephination of the frontal sinuses revealed a space-occupying mass that was interpreted on histologic examination to be lymphosarcoma. Other evidence of neoplasia was not discovered on gross necropsy or histologic examination. Primary lymphosarcoma has not been described at this location in cows. Clinically it resembles chronic frontal sinusitis, and trephination may be necessary to differentiate the 2 diseases.
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PMID:Lymphosarcoma of the frontal sinus and nasal passage in a cow. 982 47

The pleiotropic weaver disease is caused by the mutation of a single amino acid in the G-protein-linked inwardly rectifying K+ channel, GIRK2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testicular cells, which produce ataxia, fine tremors, and sterility, respectively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is observed and wv/+ males become sterile at 3.5 months of age. Abnormal influxes of Na+ and Ca2+ have been linked to cerebellar cell death in wv/wv animals, but it's not clear whether similar changes are observed in wv/+ animals. To discover whether changes in K+-channel function or intracellular Ca2+ concentrations ([Ca2+]i) play a role in the augmented cell loss observed in wv/+ animals when compared with +/+ animals, we studied cultured cerebellar granule cells prepared from either wv/+ or +/+ animals. Resting [Ca2+]i was elevated in wv/+ relative to +/+ animals. Further, depolarizations of cells with elevated K+ solutions elicited much smaller changes in [Ca2+]i in wv/+ animals than in +/+ animals, presumably due to altered GIRK2 channel function. Both wv/+ and +/+ cells showed similar changes in [Ca2+]i when cells were depolarized by glutamate (1 mM), suggesting that both glutamate receptors and Ca2+ channels were unchanged in wv/ + animals. In summary, our results suggest that wv/+ cerebellar granule cells exhibit elevated resting [Ca2+]i levels and altered K+-channel function, which may contribute to the developmental abnormalities and increased cell death observed.
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PMID:Altered responses to potassium in cerebellar neurons from weaver heterozygote mice. 986 Feb 68

Tottering mice inherit a recessive mutation of the calcium channel alpha1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block L-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced tottering mouse motor episodes. Conversely, the L-type calcium channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated that L-type calcium channel alpha1C subunit mRNA expression was up-regulated in the Purkinje cells of tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of L-type calcium channels in tottering mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in tottering mice, L-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of L-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.
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PMID:L-type calcium channels contribute to the tottering mouse dystonic episodes. 988 94


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