Spinocerebellar Ataxia 17 (TBP)
| Dred_ID | RD00006 |
| OMIM ID | 607136 |
| Disease name | Spinocerebellar Ataxia 17 |
| Alternative names | SCA17, HDL4, Huntington Disease-like 4 |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Skin diseases, Eye diseases, Mental diseases, Ear diseases, Metabolic diseases, Fetal diseases, Liver diseases |
| Phenotype | Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course |
| Miscellaneouse | OMIM: progressive disorder median age at onset 23 years psychiatric symptoms may be the presenting sign normal alleles have 25 to 44 repeats mutant alleles have 47 to 63 repeats those with intermediate repeat expansions show reduced penetrance |
| Prevalence | Prevalence: <1/1000000 (Worldwide),<1/1000000 (Japan),1-9/1000000 (United Kingdom); [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | TBP |
| Alias symbols | HDL4; GTF2D; SCA17; TFIID; GTF2D1 |
| Gene name | TATA box binding protein |
| Gene map locus | 6q27; chr6:170,554,302-170,572,870(+) |
| Ensembl Gene ID | ENSG00000112592 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes TBP, the TATA-binding protein. A distinctive feature of TBP is a long string of glutamines in the N-terminus. This region of the protein modulates the DNA binding activity of the C terminus, and modulation of DNA binding affects the rate of transcription complex formation and initiation of transcription. The number of CAG repeats encoding the polyglutamine tract is usually 25-42, and expansion of the number of repeats to 45-66 increases the length of the polyglutamine string and is associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2016] |
| Repeat unit | CAG |
| Normal repeat copies | 25-44 |
| Pathogenic repeat copies | ≥47 |
| Gene | TBP |
| Repeat location | CDS |
| Chromosome locus | chr6:170561926-170562024 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | Over expression of full-length-mutant TBP and truncated-mutant TBP lacking the DNA-binding domains (DBDs) was found to cause formation of inclusions, suggesting that insoluble aggregates are causative factors and that the neurotoxicity of mutant TBP is independent of DNA binding [69]. Thus, the pathogenesis of SCA17 seems similar to that of other polyQ diseases. On the other hand, whether or not expanded polyQ tracts affect the function of TBP has yet to be comprehensively addressed. TBP is a general transcription factor, essential for formation of the transcription preinitiation complex and transcription of RNA polymerases I, II and III (Pol I, II and III). Aberrant TBP activity is expected to profoundly affect normal cellular function. Inactivation of TBP in mice causes downregulation of Pol I and Pol III transcription, growth arrest and cell death. Friedmann et al. have reported that polyQ expansion reduces in vitro binding of TBP to DNA. Furthermore, they observed that polyQ-expanded TBP fragments, which were incapable of binding DNA, formed nuclear inclusions and caused a severe neurological phenotype in transgenic mice. [By PMID: 29427105] |
| Pathway annotation | Reactome, KEGG |
| PMID | 14985389 |
| Authors | Bauer P, Laccone F, Rolfs A, Wüllner U, Bösch S, Peters H, Liebscher S, Scheible M, Epplen JT, Weber BH, Holinski-Feder E, Weirich-Schwaiger H, Morris-Rosendahl DJ, Andrich J, Riess O |
| Title | Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington's disease-like phenotype |
| Journal | J Med Genet. 41(3):230-2 |
| Year | 2004 |
| PMID | 18043721 |
| Authors | Gao R, Matsuura T, Coolbaugh M, Zühlke C, Nakamura K, Rasmussen A, Siciliano MJ, Ashizawa T, Lin X |
| Title | Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17 |
| Journal | Eur J Hum Genet. 16(2):215-22 |
| Year | 2008 |