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)

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the novel competitive NMDA receptor antagonist CGP 39551 on levels of 11 amino acids, including several excitatory and inhibitory neurotransmitters, were studied in 12 brain regions of rats. Both drugs were administered at doses which produced comparable behavioural effects (ataxia, hyperactivity). Amino acids were determined in brain tissue by high-performance liquid chromatography after o-phthaldialdehyde precolumn derivatization. MK-801 (0.1 mg/kg, i.p.) moderately increased the concentration of glutamate and GABA in several brain regions. Other amino acids (glutamine, taurine, asparagine, alanine, serine) were only altered in single brain regions, or were not altered at all (aspartate, glycine, threonine, arginine). In contrast to MK-801, CGP 39551 (10 mg/kg, i.p.) increased glutamate levels only in the cerebellum, and produced no significant alterations in levels of GABA. The data demonstrate differences in alterations of amino acid levels in response to competitive and non-competitive NMDA receptor antagonists and support the assumption that competitive NMDA antagonists may be more selective than non-competitive antagonists.
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PMID:Regional alterations in brain amino acids after administration of the N-methyl-D-aspartate receptor antagonists MK-801 and CGP 39551 in rats. 167 57

Young Bobwhite quail (Colinus virginianus) were fed low and adequate protein purified diets with and without excess methionine to evaluate factors affecting methionine toxicity. Growth of quail fed an adequate protein (27%) diet, without supplemental glycine, was depressed by 1.75% and 2.25% excess methionine. Supplemental glycine (.3%) alleviated growth depression caused by 2.25% excess methionine. Quail fed 1.75% and 2.25% excess methionine developed signs of toxicity characterized by weakness, a lowered, outstretched neck when moving, and ataxia. In addition, quail would fall on their sides when disturbed and spin with their heads retracted. These conditions were transient in nature. Growth of quail fed a low protein (18.9%) diet was depressed by 1% and 1.5% excess methionine and DL-homocystine. Quail fed 1% and 1.5% excess methionine in this diet also developed signs of toxicity, the incidence of which was greater and the duration longer than occurred with quail fed adequate protein. Supplementing a low protein (20.15%) diet with .3% or .6% glycine or threonine or a combination of these amino acids did not alleviate growth depression caused by 1.5% excess methionine; however, 2% and 3% supplemental glycine were somewhat effective. Supplements of glycine (2%, 3%) and threonine (1%) completely reversed growth depression from 1% excess methionine but did not influence growth of controls, indicating that both amino acids counteract methionine toxicity. Both glycine and threonine alone improved growth by about the same extent in diets with 1% or 1.5% excess methionine; however, these amino acids alleviated less than 30% of the growth depression resulting from 1.5% excess methionine. The effectiveness of glycine in alleviating methionine toxicity in a low protein diet was decreased, and hemoglobin levels were depressed with 1.5% excess methionine compared to less amounts.
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PMID:Factors influencing methionine toxicity in young bobwhite quail. 678 33

Three adult patients with acid beta-galactosidase deficiency/GM1 gangliosidosis who were from two unrelated families of Scandinavian descent were found to share a common point mutation in the coding region of the corresponding gene. The patients share common clinical features, including early dysarthria, mild ataxia, and bone abnormalities. When cDNA from the two patients in family 1 was PCR amplified and sequenced, most (39/41) of the clones showed a C-to-T transition (C-->T) at nucleotide 245 (counting from the initiation codon). This mutation changes the codon for Thr(ACG) to Met(ATG). Mutant and normal sequences were also found in that position in genomic DNA, indicating the presence of another mutant allele. Genomic DNA from the patient in family 2 revealed the same point mutation in one allele. It was determined that in each family only the father carried the C-->T mutation. Expression studies showed that this mutation produced 3%-4% of beta-galactosidase activity, confirming its deleterious effects. The cDNA clones from the patients in family 1 that did not contain the C-->T revealed a 20-bp insertion of intronic sequence between nucleotides 75 and 76, the location of the first intron. Further analysis showed the insertion of a T near the 5' splice donor site which led to the use of a cryptic splice site. It appears that the C-->T mutation results in enough functional enzyme to produce a mild adult form of the disease, even in the presence of a second mutation that likely produces nonfunctional enzyme.
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PMID:Mutations in the lysosomal beta-galactosidase gene that cause the adult form of GM1 gangliosidosis. 819 23

Myotonic dystrophy (DM) is genetically characterized by abnormal expansion of an unstable CTG trinucleotide repeat, located in the 3'-untranslated region of mRNA encoding the family of serine-threonine protein kinases. DNA extracted from various organs of patients with DM was analyzed by the Southern blotting method. We identified differently expanded bands in DNAs from various tissues from patients with DM. In studying the length of the CTG repeat in different regions of the brain, we found a noticeably small increase in repeat length in the cerebellum compared with other tissues. While this phenomenon has been reported in other triplet repeat diseases such as Huntington disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy, we are the first to describe it in DM. Although the mechanism of expansion of the triplet repeat remains to be defined, the tissue-dependent somatic mosaicism suggests that its occurrence may depend on the differentiated state of each tissue.
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PMID:Small increase in triplet repeat length of cerebellum from patients with myotonic dystrophy. 869 28

Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous Lurcher mice (Lc/+) display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis. We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta2 glutamate receptor gene (GluR delta2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.
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PMID:Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. 928 76

The voltage-gated sodium channel SCN8A is associated with inherited neurological disorders in the mouse that include ataxia, dystonia, severe muscle weakness, and paralysis. We report the complete coding sequence and exon organization of the human SCN8A gene. The predicted 1980 amino acid residues are distributed among 28 exons, including two pairs of alternatively spliced exons. The SCN8A protein is evolutionarily conserved, with 98.5% amino acid sequence identity between human and mouse. Consensus sites for phosphorylation of serine/threonine and tyrosine residues are present in cyoplasmic loop domains. The polymorphic (CA)n microsatellite marker D12S2211, with PIC = 0.68, was isolated from intron 10C of SCN8A. Single nucleotide polymorphisms in intron 19 and exon 22 were also identified. We localized SCN8A to chromosome band 12q13.1 by physical mapping on a YAC contig. The cDNA clone CSC-1 was reported by others to be a cardiac-specific sodium channel, but sequence comparison demonstrates that it is derived from exon 24 of human SCN8A. The genetic information described here will be useful in evaluating SCN8A as a candidate gene for human neurological disease.
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PMID:Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. 982 31

Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous lurcher mice (Lc/+) display ataxia due to a selective, cell-autonomous, apoptotic death of 90% of cerebellar Purkinje cells during postnatal development. Homozygous lurcher mice (Lc/Lc) die shortly after birth due to massive loss of mid- and hindbrain neurons during late embryogenesis. We identified the mutations responsible for neurodegeneration in two independent Lc alleles as identical G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta 2 glutamate receptor gene (GluRE2). Lc/+ Purkinje cells displayed a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta 2Lc protein in Xenopus oocytes confirmed these results, demonstrating that lurcher is an inherited neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Further characterization of GluR delta 2 signaling and the activation of apoptotic death in Lc Purkinje cells have begun to yield mechanistic insights into this neurodegenerative disease, and to highlight its relationship to neuronal loss following ischemia.
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PMID:GluR delta 2 and the development and death of cerebellar Purkinje neurons in lurcher mice. 1041 27

A mutation of alanine to threonine in the III S4-S5 linker of the mouse Scn8a sodium channel has previously been identified as causing the ataxia in med(jo) mice. The electrophysiological effects of this mutation in Scn8a sodium channels were characterized in Xenopus oocytes. The med(jo) mutation caused a 10 mV positive shift in the voltage dependence of activation, without any significant changes in the kinetics of either inactivation or recovery from inactivation. The shift in the voltage dependence of activation observed for the mutant channel would reduce the spontaneous activity of Purkinje cells and lead to a decrease in output from the cerebellum, which is consistent with the phenotype of cerebellar ataxia observed in med(jo) mice.
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PMID:A mutation that causes ataxia shifts the voltage-dependence of the Scn8a sodium channel. 1054 17

We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of > or =16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts. Noncoding CAG, CTG, and ATTCT expansions are responsible for three other SCAs. Approximately 30% of families with SCA do not have linkage to the known loci. We recently mapped the locus for an AD SCA in a family (AT08) to chromosome 19q13.4-qter. A particularly compelling candidate gene, PRKCG, encodes protein kinase C gamma (PKC gamma), a member of a family of serine/threonine kinases. The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions. Three different nonconservative missense mutations in highly conserved residues in C1, the cysteine-rich region of the protein, were found in family AT08, another familial case, and a sporadic case. The mutations cosegregated with disease in both families. Structural modeling predicts that two of these amino acid substitutions would severely abrogate the zinc-binding or phorbol ester-binding capabilities of the protein. Immunohistochemical studies on cerebellar tissue from an affected member of family AT08 demonstrated reduced staining for both PKC gamma and ataxin 1 in Purkinje cells, whereas staining for calbindin was preserved. These results strongly support a new mechanism for neuronal cell dysfunction and death in hereditary ataxias and suggest that there may be a common pathway for PKC gamma-related and polyglutamine-related neurodegeneration.
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PMID:Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. 1264 68

Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B'') subunits. Variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. The Bbeta regulatory subunit gene is mutated in spinocerebellar ataxia type 12, and one of its splice variants, Bbeta2, targets PP2A to mitochondria to promote apoptosis in PC12 cells (Dagda, R. K., Zaucha, J. A., Wadzinski, B. E., and Strack, S. (2003) J. Biol. Chem. 278, 24976-24985). Here, we report that Bbeta2 is localized to the outer mitochondrial membrane by a novel mechanism, combining a cryptic mitochondrial import signal with a structural arrest domain. Scanning mutagenesis demonstrates that basic and hydrophobic residues mediate mitochondrial association and the proapoptotic activity of Bbeta2. When fused to green fluorescent protein, the N terminus of Bbeta2 acts as a cleavable mitochondrial import signal. Surprisingly, full-length Bbeta2 is not detectably cleaved and is retained at the outer mitochondrial membrane, even though it interacts with the TOM22 import receptor, as shown by luciferase complementation in intact cells. Mutations that open the C-terminal beta-propeller of Bbeta2 facilitate mitochondrial import, indicating that this rigid fold acts as a stop-transfer domain by resisting the partial unfolding step prerequisite for matrix translocation. Because hybrids of prototypical import and beta-propeller domains recapitulate this behavior, we predict the existence of other similarly localized proteins and a selection against highly stable protein folds in the mitochondrial matrix. This unfolding-resistant targeting to the mitochondrial translocase is necessary but not sufficient for the proapoptotic activity of Bbeta2, which also requires association with the rest of the PP2A holoenzyme.
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PMID:Unfolding-resistant translocase targeting: a novel mechanism for outer mitochondrial membrane localization exemplified by the Bbeta2 regulatory subunit of protein phosphatase 2A. 1592 82


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