Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20226 (TATA-binding protein)
 1,297 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia type 17 (SCA17) is a dominant progressive neurodegenerative disorder, caused by a triplet repeat expansion within the TATA-binding protein. As well as ataxia and dementia, Parkinsonism and dystonia are common in SCA17. In some pedigrees focal dystonia in the absence of ataxia has been described as a main clinical feature. To evaluate the relevance of SCA17 mutations for primary dystonia, we examined the TBP repeat expansion in a series of 288 patients with different subtypes of primary torsion dystonia. We did not find any repeat sizes in the pathogenic range. We conclude that the SCA17 repeat expansion is not a common cause of familial and sporadic dystonia.
 ...
PMID:Mutation at the SCA17 locus is not a common cause of primary dystonia. 1550 3

We report on a 50-year-old woman who presented with an 8-year history of involuntary movements, unsteadiness, and cognitive decline. Examination revealed multidomain cognitive deficits, jerky ocular pursuit movements, hypometric saccades, gaze impersistence, dysarthria, upper limb dystonia, and widespread chorea. TATA-binding protein gene test revealed trinucleotide expansion allele sizes of 47 and 39 repeats, confirming the diagnosis of spinocerebellar ataxia type 17 (SCA-17). Magnetic resonance imaging (MRI) showed marked cerebellar atrophy and putaminal rim hyperintensity. This is the first case of SCA-17 reported to show MRI signal change in the basal ganglia, and extends the phenotypic manifestation of SCA-17.
 ...
PMID:Spinocerebellar ataxia type 17: extension of phenotype with putaminal rim hyperintensity on magnetic resonance imaging. 1603 35

Extrapyramidal signs are a main feature of spinocerebellar ataxia 17 (SCA17). However, the extent of dopaminergic dysfunction and its correlation with parkinsonian signs are not fully understood. In order to define this, we investigated five subjects from three different families with a pathological CAG/CAA expansion in the TATA-binding protein gene (SCA17), ranging from asymptomatic carrier to patient with advanced disease, by FP-CIT SPECT. Nigrostriatal dysfunction was present in patients manifesting a fully developed phenotype but not in preclinical and early stages. Dopamine transporter reduction was symmetrical and uniform in caudate and putamen and it correlated with the clinical severity of ataxia.
 ...
PMID:Characterization of nigrostriatal dysfunction in spinocerebellar ataxia 17. 1653 53

SCA17 is a rare type of autosomal dominant spinocerebellar ataxia caused by a CAG/CAA expansion in the gene encoding the TATA-binding protein (TBP). We screened for triplet expansion in the TBP gene 110 subjects with progressive cerebellar ataxia and 94 subjects with Huntington-like phenotype negative at specific molecular tests. SCA17 mutation-positive subjects were found in both groups of patients. Expanded alleles with > or = 44 CAG/CAA repeats were identified in 11 individuals and in 4 non-symptomatic relatives. Eleven de novo diagnosed patients and four patients previously reported underwent extensive clinical, neuroradiological and oculographic examination. Cerebellar signs and symptoms were present in all cases; 80% of the patients had mild to severe cognitive deficits; 66% of patients showed choreic movements; pyramidal signs, bradykinesia and dystonia were observed in approx 50% of the cases. MRI demonstrated cortical and cerebellar atrophy in all patients, whereas neurophysiological examination excluded signs of peripheral nervous system involvement. Oculographic examinations were performed in 9 out of 15 patients and showed a distinct pattern of oculomotor abnormalities, characterized by impairment of smooth pursuit, defects in the saccade accuracy, normal saccade velocity, hyperreflexia of vestibuloocular reflexes, and absence of nystagmus. In summary, this study presents one of the largest series of SCA17 patients in Europe. In our group of patients, SCA17 represents the third most frequent SCA genotype. Our clinical data confirm the large variability in SCA17 phenotypic presentation, and indicate that a peculiar combination of neuroradiological, electrophysiological and oculomotor findings is recognizable in SCA17.
 ...
PMID:Spinocerebellar ataxia type 17 (SCA17): oculomotor phenotype and clinical characterization of 15 Italian patients. 1793 76

TATA-binding protein (TBP) is essential for eukaryotic gene transcription. Human TBP contains a polymorphic polyglutamine (polyQ) domain in its N terminus and a DNA-binding domain in its highly conserved C terminus. Expansion of the polyQ domain to >42 glutamines typically results in spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder that resembles Huntington disease. Our recent studies have demonstrated that polyQ expansion causes abnormal interaction of TBP with the general transcription factor TFIIB and induces neurodegeneration in transgenic SCA17 mice (Friedman, M. J., Shah, A. G., Fang, Z. H., Ward, E. G., Warren, S. T., Li, S., and Li, X. J. (2007) Nat. Neurosci. 10, 1519-1528). However, it remains unknown how polyQ expansion influences DNA binding by TBP. Here we report that polyQ expansion reduces in vitro binding of TBP to DNA and that mutant TBP fragments lacking an intact C-terminal DNA-binding domain are present in transgenic SCA17 mouse brains. polyQ-expanded TBP with a deletion spanning part of the DNA-binding domain does not bind DNA in vitro but forms nuclear aggregates and inhibits TATA-dependent transcription activity in cultured cells. When this TBP double mutant is expressed in transgenic mice, it forms nuclear inclusions in neurons and causes early death. These findings suggest that the polyQ tract affects the binding of TBP to promoter DNA and that polyQ-expanded TBP can induce neuronal toxicity independent of its interaction with DNA.
 ...
PMID:Polyglutamine expansion reduces the association of TATA-binding protein with DNA and induces DNA binding-independent neurotoxicity. 1821 37

A persistent mystery about the ataxias has been why mutations in genes--many of which are expressed widely in the brain--primarily cause ataxia, and not, for example, epilepsy or dementia. Why should a polyglutamine stretch in the TATA-binding protein (that is important in all cells) particularly disrupt cerebellar coordination? We propose that advances in the genetics of cerebellar ataxias suggest a rational hypothesis for how so many different genes lead to predominantly cerebellar defects. We argue that the unifying feature of many genes involved in cerebellar ataxias is their impact on the signaling protein ITPR1 (inositiol 1,4,5-triphosphate receptor type 1), that underlies coincidence detection in Purkinje cells and could play an important role in cerebellar coordination.
 ...
PMID:Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. 2022 42

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant inherited disorder characterized by degeneration of spinocerebellar tracts and selected brainstem neurons owing to the expansion of a CAG repeat of the human TATA-binding protein (hTBP) gene. To gain insight into the pathogenesis of this hTBP mutation, we generated transgenic mice with the mutant hTBP gene driven by the Purkinje specific protein (Pcp2/L7) gene promoter. Mice with the expanded hTBP allele developed ataxia within 2-5 months. Behavioral analysis of L7-hTBP transgenic mice showed reduced fall latency in a rotarod assay. Purkinje cell degeneration was identified by immunostaining of calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred in the transgenic cerebellum, accompanied by up-regulation of GFAP and Iba1. The L7-hTBP transgenic mice were thus confirmed to recapitulate the SCA17 phenotype and were used as a disease model to explore the potential of granulocyte-colony stimulating factor in SCA17 treatment. Our results suggest that granulocyte-colony stimulating factor has a neuroprotective effect in these transgenic mice, ameliorating their neurological and behavioral deficits. These data indicate that the expression of the mutant hTBP in Purkinje cells is sufficient to produce cell degeneration and an ataxia phenotype, and constitutes a good model for better analysis of the neurodegeneration in SCA17.
 ...
PMID:Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. 2155 23

The SCA17 clinical phenotype includes characteristics associated with cerebellar and cortical atrophy such as ataxia, dementia, epilepsy, chorea and parkinsonian features. Here we describe the case of a 38-year-old male presenting with ataxia, cognitive impairment and seizures, who was found to carry 43 repeats on one allele of the TATA-binding protein (TBP) gene. Therefore, genetic analysis of TBP gene triplets was performed on the patient's entire family, identifying three asymptomatic carriers of the same allele. A neuroradiological phenotype appeared to segregate with this allele, suggesting that it may play at least a contributory role in the determination of SCA17.
 ...
PMID:Early-onset SCA17 with 43 TBP repeats: expanding the phenotype? 2171 Jan 29

Spinocerebellar ataxias are a group of rare and heterogeneous autosomal dominant disorders characterized by progressive ataxia and other features. Spinocerebellar ataxia 17 (SCA17) is one of the 32 subtypes described to date and is secondary to CAG/CAA repeat expansion in the gene coding for the TATA-box binding protein (TBP). SCA17 is clinically heterogeneous and typically presents with slowly evolving ataxia, dysarthria, dementia, depression, and other movement disorders such as chorea. More than 41 CAG/CAA repeats are considered diagnostic of SCA17, with more than 49 being associated with full penetrance. We report one patient presenting with isolated rapidly evolving ataxia who was found to have 44 CAG/CAA repeats in the TBP gene. This suggests that, while SCA17 typically slowly progresses over years, its repertoire of presentations should be expanded to include rapidly progressive isolated ataxia resembling paraneoplastic disorders or prion disease.
...
PMID:From normal gait to loss of ambulation in 6 months: a novel presentation of SCA17. 2347 85

Spinocerebellar Ataxia type 17 (SCA17) is an autosomal dominantly inherited, neurodegenerative disease characterized by ataxia, involuntary movements, and dementia. A novel SCA17 mouse model having a 71 polyglutamine repeat expansion in the TATA-binding protein (TBP) has shown age related motor deficit using a classic motor test, yet concomitant weight increase might be a confounding factor for this measurement. In this study we used an automated home cage system to test several motor readouts for this same model to confirm pathological behavior results and evaluate benefits of automated home cage in behavior phenotyping. Our results confirm motor deficits in the Tbp/Q71 mice and present previously unrecognized behavioral characteristics obtained from the automated home cage, indicating its use for high-throughput screening and testing, e.g. of therapeutic compounds.
...
PMID:Automated home cage assessment shows behavioral changes in a transgenic mouse model of spinocerebellar ataxia type 17. 2366 19


<< Previous 1 2 3 Next >>