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 inositol 1,4,5-trisphosphate (InsP3) receptor acts as an InsP3-gated Ca2+ release channel in a variety of cell types. Type 1 InsP3 receptor (IP3R1) is the major neuronal member of the IP3R family in the central nervous system, predominantly enriched in cerebellar Purkinje cells but also concentrated in neurons in the hippocampal CA1 region, caudate-putamen, and cerebral cortex. Here we report that most IP3R1-deficient mice generated by gene targeting die in utero, and born animals have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. An electroencephalogram showed that they suffer from epilepsy, indicating that IP3R1 is essential for proper brain function. However, observation by light microscope of the haematoxylin-eosin staining of the brain and peripheral tissues of IP3R1-deficient mice showed no abnormality, and the unique electrophysiological properties of the cerebellar Purkinje cells of IP3R1-deficient mice were not severely impaired.
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PMID:Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. 853 67

The opisthotonos (opt) mutation arose spontaneously in a C57BL/Ks-db2J colony and is the only known, naturally occurring allele of opt. This mutant mouse was first identified based on its ataxic and convulsive phenotype. Genetic and molecular data presented here demonstrate that the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) protein, which serves as an IP3-gated channel to release calcium from intracellular stores, is altered in the opt mutant. A genomic deletion in the IP3R1 gene removes two exons from the IP3R1 mRNA but does not interrupt the translational reading frame. The altered protein is predicted to have lost several modulatory sites and is present at markedly reduced levels in opt homozygotes. Nonetheless, a strong calcium release from intracellular stores can be elicited in cerebellar Purkinje neurons treated with the metabotropic glutamate receptor (mGluR) agonist quisqualate (QA). QA activates Group 1 mGluRs linked to GTP-binding proteins that stimulate phospholipase C and subsequent production of the intracellular messenger IP3, leading to calcium mobilization via the IP3R1 protein. The calcium response in opt homozygotes shows less attenuation to repeated QA application than in control littermates. These data suggest that the convulsions and ataxia observed in opt mice may be caused by the physiological dysregulation of a functional IP3R1 protein.
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PMID:The type 1 inositol 1,4,5-trisphosphate receptor gene is altered in the opisthotonos mouse. 898 86

Cerebellar Purkinje cells (PCs) from spinocerebellar ataxia type 1 (SCA1) transgenic mice develop dendritic and somatic atrophy with age. Inositol 1,4,5-trisphosphate receptor type 1 and the sarco/endoplasmic reticulum Ca(2+) ATPase pump, which regulate [Ca(2+)](i), are expressed at lower levels in these cells compared with the levels in cells from wild-type (WT) mice. To examine PCs in SCA1 mice, we used whole-cell patch clamp recording combined with fluorometric [Ca(2+)](i) and [Na(+)](i) measurements in cerebellar slices. PCs in SCA1 mice had Na(+) spikes, Ca(2+) spikes, climbing fiber (CF) electrical responses, parallel fiber (PF) electrical responses, and metabotropic glutamate receptor (mGluR)-mediated, PF-evoked Ca(2+) release from intracellular stores that were qualitatively similar to those recorded from WT mice. Under our experimental conditions, it was easier to evoke the mGluR-mediated secondary [Ca(2+)](i) increase in SCA1 PCs. The membrane resistance of SCA1 PCs was 3.3 times higher than that of WT cells, which correlated with the 1.7 times smaller cell body size. Most SCA1 PCs (but not WT) had a delayed onset (about 50--200 ms) to Na(+) spike firing induced by current injection. This delay was increased by hyperpolarizing prepulses and was eliminated by 4-aminopyridine, which suggests that this delay was due to enhancement of the A-like K(+) conductance in the SCA1 PCs. In response to CF stimulation, most PCs in mutant and WT mice had rapid, widespread [Ca(2+)](i) changes that recovered in <200 ms. Some SCA1 PCs showed a slow, localized, secondary Ca(2+) transient following the initial CF Ca(2+) transient, which may reflect release of Ca(2+) from intracellular stores. Thus, with these exceptions, the basic physiological properties of mutant PCs are similar to those of WT neurons, even with dramatic alteration of their morphology and downregulation of Ca(2+) handling molecules.
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PMID:Calcium dynamics and electrophysiological properties of cerebellar Purkinje cells in SCA1 transgenic mice. 1128 96

The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of disorders. Ten responsible genes have been identified for spinocerebellar ataxia types SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12 and SCA17, and dentatorubral pallidoluysian atrophy (DRPLA). The mutation is caused by an expansion of a CAG, CTG or ATTCT repeat sequence of these genes. Six additional loci, SCA4, SCA5, SCA11, SCA13, SCA14 and SCA16 have also been mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic aetiologies of at least 20% of ADCA have yet to be elucidated. We ascertained and clinically characterized a four-generation Chinese pedigree segregating an autosomal dominant phenotype for cerebellar ataxia. Direct mutation analysis, linkage analysis for all known SCA loci and a genome-wide linkage study were performed. Direct mutation analysis excluded SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and DRPLA, and genetic linkage analysis excluded SCA4, 5, 11, 13, 14 and 16. The genome-wide linkage study suggested linkage to a locus on chromosome 1p21-q23, with the highest two-point LOD score at D1S1167 (Zmax = 3.46 at theta = 0.00). Multipoint analysis and haplotype reconstruction traced this novel SCA locus (SCA22) to a 43.7-cM interval flanked by D1S206 and D1S2878 (Zmax = 3.78 under four liability classes, and 2.67 using affected-only method). The age at onset ranged from 10 to 46 years. All affected members had gait ataxia with variable features of dysarthria and hyporeflexia. Head MRI showed homogeneous atrophy of the cerebellum without involvement of the brainstem. In six parent-child pairs, median onset occurred 10 years earlier in offspring than in their parents, suggesting anticipation. This family is distinct from other families with SCA and is characterized by a slowly progressive, pure cerebellar ataxia.
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PMID:A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. 1467 32

We have studied a large Australian kindred with a dominantly inherited pure cerebellar ataxia, SCA15. The disease is characterised by a very slow rate of progression in some family members, and atrophy predominantly of the superior vermis, and to a lesser extent the cerebellar hemispheres. Repeat expansion detection failed to identify either a CAG/CTG or ATTCT/AGAAT repeat expansions segregating with the disease in this family. A genome-wide scan revealed significant evidence for linkage to the short arm of chromosome 3. The highest two-point LOD score was obtained with D3S3706 (Z = 3.4, theta = 0.0). Haplotype analysis identified recombinants that placed the SCA15 locus within an 11.6-cM region flanked by the markers D3S3630 and D3S1304. The mouse syntenic region contains two ataxic mutants, itpr1-/- and opt, affecting the inositol 1,4,5-triphosphate type 1 receptor, ITPR1 gene. ITPR1 is predominantly expressed in the cerebellar Purkinje cells. Mutation analysis from two representative affected family members excluded the coding region of the ITPR1 gene from being involved in the pathogenesis of SCA15. Thus, the itpr1-/- and opt ITPR1 mouse mutants, which each result in ataxia, are not allelic to the human SCA15 locus.
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PMID:Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant. 1282 38

The authors identified two Japanese spinocerebellar ataxia (SCA) families characterized by postural and action tremor and a very slow progression rate. A genome-wide linkage analysis revealed linkage to chromosome 3p26.1-25.3 with the highest multipoint lod score at D3S3728 (Zmax = 3.31 at theta = 0.00). The candidate region was 14.7 cM flanked by D3S1620 and D3S3691, which was partly overlapping with the locus of SCA15 characterized by pure cerebellar ataxia. Despite the difference in phenotypes, there remains a possibility that the causative gene for these Japanese SCA is allelic to SCA15.
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PMID:Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus. 1498 Nov 89

PMCA2, a major calcium pump, is expressed at particularly high levels in Purkinje neurons. Accordingly, PMCA2-null mice exhibit ataxia suggesting cerebellar pathology. It is not yet known how changes in PMCA2 expression or activity affect molecular pathways in Purkinje neurons. We now report that the levels of metabotropic glutamate receptor 1 (mGluR1), which plays essential roles in motor coordination, synaptic plasticity, and associative learning, are reduced in the cerebellum of PMCA2-null mice as compared to wild type littermates. The levels of inositol 1,4,5-triphosphate receptor type 1 (IP3R1), an effector downstream to mGluR1, which mediates intracellular calcium signaling, and the expression of Homer 1b/c and Homer 3, scaffold proteins that couple mGluR1 to IP3R1, are also reduced in somata and dendrites of some Purkinje cell subpopulations. In contrast, no alterations occur in the levels of mGluR1 and its downstream effectors in the hippocampus, indicating that the changes are region specific. The reduction in cerebellar mGluR1, IP3R1 and Homer 3 levels are neither due to a generic decrease in Purkinje proteins nor extensive dendritic loss as immunoreactivity to total and non-phosphorylated neurofilament H (NFH) is increased in Purkinje dendrites and microtubule associated protein 2 (MAP2) staining reveals a dense dendritic network in the molecular layer of the PMCA2-null mouse cerebellum. PMCA2 coimmunoprecipitates with mGluR1, Homer 3 and IP3R1, suggesting that the calcium pump is a constituent of the mGluR1 signaling complex. Our results suggest that the decrease in the expression of mGluR1 and its downstream effectors and perturbations in the mGluR1 signaling complex in the absence of PMCA2 may cumulatively result in aberrant metabotropic glutamate receptor signaling in Purkinje neurons leading to cerebellar deficits in the PMCA2-null mouse.
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PMID:Molecular alterations in the cerebellum of the plasma membrane calcium ATPase 2 (PMCA2)-null mouse indicate abnormalities in Purkinje neurons. 1715 Mar 72

To confirm the incidence of SCA16 in Japan, we screened DNA samples from a number of patients of ataxia of unknown etiology for the substitution. We examined a total of 323 DNA samples from Japanese patients with inherited spinocerebellar ataxia. We found no 317-base pair band in the patients with ataxia of unknown etiology. It seemed that this mutation (c.4256C>T) is rare in Japanese patients with inherited spinocerebellar ataxia. Mutations in other populations should be analyzed. Pathological examinations and molecular biological examinations are needed to confirm that this mutation is a true cause of SCA16.
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PMID:The CNTN4 c.4256C>T mutation is rare in Japanese with inherited spinocerebellar ataxia. 1791 52

We have previously mapped autosomal dominant spinocerebellar ataxia (SCA) 16 to 3p26, overlapping with the locus of SCA15. Recently, partial deletions of ITPR1 and the neighbouring SUMF1 in the SCA15 and two additional families were reported. In the present study we determined the copy number of these genes by real time quantitative polymerase chain reaction (PCR) and found a heterozygous deletion of exons 1-48 of ITPR1, but not SUMF1 in SCA16. Breakpoint analysis revealed that the size of the deletion is 313,318 bp and the telomeric breakpoint is located in the middle of their intergenic region. Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15.
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PMID:Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16. 1831 Feb 70

Spinocerebellar ataxia type 15 and 16 (SCA15/16) are autosomal dominant cerebellar ataxias that are slowly progressive with a predominantly pure ataxia phenotype (ADCA III). The locus for SCA15 was first mapped to 3p24.2-3pter and subsequently full or partial deletions in the inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene were identified in several ADCA III families that segregated with the disease. A single missense coding variant has been described, but the pathogenicity of this change has not been proven. We sequenced the entire coding region and flanking regions of ITPR1 in unrelated ADCA III families (n = 38) that were negative for large deletions on whole genome arrays, and for which SCAs 1, 2, 3, 6, 7, 8, 11, 12, 14, 17 and the Friedreich's ataxia expansion were excluded in all probands. Mutation at SCA5, 10, and 27 was also excluded in some families. A number of coding and noncoding polymorphisms were identified but no ITPR1 mutations were found. The results indicate that point mutations in ITPR1 are at best a rare cause of ADCA III.
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PMID:Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series. 2043 44


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