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Query: UMLS:C0007758 (cerebellar ataxia)
 3,609 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of the neuropathological mutant animals offers us great information on the development and differentiation of the nervous system. I have here introduced two examples of the analyses of the various kinds of neuropathological mutant mice. First one is the mutant mice where Purkinje neurons in the cerebellum are absent. High molecular weight protein, P400, enriched in the Purikinje cells in the cerebellum was greatly decreased in the Purkinje cell deficient mutant mice, nervous, pcd, Lurcher. We demonstrated that P400 is equivalent to IP3 receptor type 1. We found that IP3 receptor type 1 plays an important role in Ca2+ wave in fertilization and long term depression in the cerebellum which is one of the typical example of neuronal plasticity in the cerebellum. Second mutant is reeler mice where neuronal positioning in the brain is abnormal. We found CR50 antigen, reelin is the key molecule as a secreted molecule from Cajal-Retzius neuron for the neuronal positioning. We produced IP3 receptor deficient mice by gene targeting. The birth rate was one fifth of the control and the animals die before 25 postnatal days. They showed cerebellar ataxia and epileptic seizure.
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PMID:[Molecular biological analysis of the development of the mammalian central nervous system]. 957 52

An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population. An identity-by-descent mapping approach using eight patients from three interrelated Hutterite families localized the gene for this syndrome to chromosome region 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. To our knowledge, this syndrome represents the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect.
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PMID:Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. 1608 Jan 22

The reeler mouse is an autosomal recessive mutant mouse caused by mutation of the reelin gene and characterized by cerebellar ataxia. To determine whether the distribution pattern of precerebellar nuclei neurons in the brainstem of the reeler mouse changes, we injected a small volume of a replication-defective recombinant adenovirus carrying E. coli beta-galactosidase (lacZ) into the cerebellar cortex of normal and reeler mice. Five days later, the mice were transcardially perfused by a fixative solution. X-gal staining of coronal or sagittal sections of the brainstem revealed that many origins for reticulocerebellar, cuneocerebellar, trigeminocerebellar, and pontocerebellar projections were retrogradely labeled, but only a few olivocerebellar neurons were labeled. Retrogradely labeled neurons in the lateral reticular nucleus tended to locate more laterally and be more condensed into a small compartment in the reeler compared with their normal counterparts. Retrogradely labeled neurons in the external cuneate nucleus were more dorsally shifted in the reeler mice compared with their normal counterparts. We could not find any differences between the normal and reeler mice in the distribution patterns of their trigeminocerebellar projection neurons. Retrogradely labeled pontocerebellar neurons in the basilar pons of the reeler mouse were reduced in number compared with their normal counterparts in addition to being more ventrally and laterally shifted. These findings strongly suggest that the migration of some precerebellar nuclei neurons from the rhombic lip to their final loci may be obstructed in the reeler mice.
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PMID:Retrograde infection of precerebellar nuclei neurons by injection of a recombinant adenovirus into the cerebellar cortex of normal and reeler mice. 1755 44

We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2-24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C>T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.
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PMID:Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome. 1804 14

The Reelin (Reln)-deficient mouse (reeler) and the Dab1-deficient mouse (yotari) are autosomal recessive mutant mice characterized by cerebellar ataxia. Previously, we reported that Reelin and Dab1 proteins have slightly different functions during the development of the cerebral cortex. To analyze the functional roles of Reelin and Dab1 proteins in detail, we attempted to generate a reelin/Dab1 compound-mutant mouse by breeding heterozygote reeler and yotari mice. We examined the cytoarchitecture of the cerebral and cerebellar cortices and the hippocampus of wild-type (Reln ( +/+ ); Dab1 ( +/+ )), double-heterozygote (Reln ( rl/+ ); Dab1 ( yot/+ )), reeler (Reln ( rl/rl ); Dab1 ( +/+ ), Reln ( rl/rl ); Dab1 ( yot/+ )), yotari (Reln ( +/+ ); Dab1 ( yot/yot ), Reln ( rl/+ ); Dab1 ( yot/yot )), and double-compound-deficient (Reln ( rl/rl ); Dab1 ( yot/yot )) mice. Nissl staining demonstrated that no abnormality was recognized in the mice of reelin/Dab1 double-heterozygote (Reln ( rl/+ ); Dab1 ( yot/+ )). The reelin/Dab1-compound mutant mouse (Reln ( rl/rl ); Dab1 ( yot/yot )) showed histological abnormalities in the cerebral and cerebellar cortices and the hippocampus, in addition to those of reeler and yotari mice. We injected HRP into the lumbar cord of these animals with various gene compositions to examine the distribution pattern of corticospinal tract (CST) neurons. CST neurons of the reelin/Dab1-compound mutant mice were not confined to layer V, but scattered throughout the motor cortex. This quantitative and statistical analysis shows that the distribution pattern of CST neurons of the reelin/Dab1-compound mutant mouse differs from those of either of the reeler or yotari counterparts. Taken together, although Reelin/Dab1 signal transduction is a primary cascade in neurons during developmental periods, other signaling cascades (e.g., the Cdk-5/Dab1 pathway) may lie in a parallel fashion to Reelin/Dab1 signal transduction.
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PMID:Histological study in the brain of the reelin/Dab1-compound mutant mouse. 1922 60

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders characterized by hypoplasia and atrophy of the cerebellar cortex, dentate and pontine nuclei, and inferior olives. The very low density lipoprotein receptor protein is an integral part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Mutations in this receptor cause nonprogressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia. In this report, we present 3 patients from 2 different families displaying very low density lipoprotein receptor-associated pontocerebellar hypoplasia, cortical dysplasia, mental retardation, and bipedal gait. One of the siblings has also displayed dysmorphic features, as we previously reported before the identification of the genetic defect in this family.
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PMID:The very low density lipoprotein receptor-associated pontocerebellar hypoplasia and dysmorphic features in three Turkish patients. 2253 56

Dysequilibrium syndrome (DES, OMIM 224050) is a genetically heterogeneous condition that combines autosomal recessive non-progressive cerebellar ataxia with mental retardation. The subclass dysequilibrium syndrome type 1 (CAMRQ1) has been attributed to mutations in the VLDLR gene encoding the very low density lipoprotein receptor (VLDLR). This receptor is involved in the Reelin signaling pathway that guides neuronal migration in the cerebral cortex and cerebellum. Three missense mutations (c.1459G>T; p.D487Y, c.1561G>C; p.D521H and c.2117G>T; p.C706F) have been previously identified in VLDLR gene in patients with DES. However, the functional implications of those mutations are not known and therefore we undertook detailed functional analysis to elucidate the cellular mechanisms underlying their pathogenicity. The mutations have been generated by site-directed mutagenesis and then expressed in cultured cell lines. Confocal microscopy and biochemical analysis have been employed to examine the subcellular localization and functional activities of the mutated proteins relative to wild type. Our results indicate that the three missense mutations lead to defective intracellular trafficking and ER retention of the mutant VLDLR protein. This trafficking impairment prevents the mutants from reaching the plasma membrane and binding exogenous Reelin, the initiating event in Reelin signaling. Collectively, our results provide evidence that ER quality control is involved in the functional inactivation and underlying pathogenicity of these DES-associated mutations in the VLDLR.
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PMID:Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome. 2517 16

Reelin-Dab1 signaling is involved in brain development and neuronal functions. The abnormalities in the signaling through either reduction of Reelin and Dab1 gene expressions or the genomic mutations in the brain have been reported to be associated with psychiatric disorders. However, it has not been clear if the deficiency in Reelin-Dab1 signaling is responsible for symptoms of the disorders. Here, to examine the function of Reelin-Dab1 signaling in the forebrain, we generated dorsal forebrain-specific Dab1 conditional knockout mouse (Dab1 cKO) and performed a behavioral test battery on the Dab1 cKO mice. Although conventional Dab1 null mutant mice exhibit cerebellar atrophy and cerebellar ataxia, the Dab1 cKO mice had normal cerebellum and showed no motor dysfunction. Dab1 cKO mice exhibited behavioral abnormalities, including hyperactivity, decreased anxiety-like behavior, and impairment of working memory, which are reminiscent of symptoms observed in patients with psychiatric disorders such as schizophrenia and bipolar disorder. These results suggest that deficiency of Reelin-Dab1 signal in the dorsal forebrain is involved in the pathogenesis of some symptoms of human psychiatric disorders.
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PMID:Dorsal Forebrain-Specific Deficiency of Reelin-Dab1 Signal Causes Behavioral Abnormalities Related to Psychiatric Disorders. 2676 56

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.
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PMID:RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes. 2700 Jun 52

The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.
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PMID:Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37. 2993 98


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