This report describes spinocerebellar ataxia 17 (SCA17), which is a subtype of spinocerebellar ataxia; SCA17 is inherited as an autosomal dominant. The human gene implicated in this disease is TBP, which encodes TATA box-binding protein, DNA-binding subunit of the RNA polymerase II transcription factor D. Expanded (CAG)n or (CAA)n trinucleotide repeats encoding polyglutamine in TBP are associated with SCA17; SCA17 is one of a number spinocerebellar ataxias caused by expansion of such repeats within the coding region of the causative gene. There is one high-scoring fly ortholog, Tbp, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. Dmel\Tbp is orthologous to a second human gene, TBPL2.
Multiple UAS constructs of the human gene Hsap\TBP have been introduced into flies, including wild-type TBP, and TBP genes with expanded polyglutamine repeats. Transgenic flies expressing a mutant Hsap\TBP protein with an expanded polyQ tract exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Expression in the eye results in a neurodegenerative phenotype; this phenotype has been used to assess genetic interactions.
Variant(s) implicated in human disease tested (as transgenic human gene, TBP): Q58_Q95 (CAG)n EXPANSION; UAS-TBP constructs with differing numbers of the pathological trinucleotide repeat have been created.
Animals homozygous for loss-of-function alleles of Dmel\Tbp die during larval stages. Heterozygous animals can survive to adulthood without obvious morphological defects, but suffer severe locomotor defects and a shortened lifespan. Physical and genetic interactions for Dmel\Tbp have been reported; see below and in the gene report for Tbp.
Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).
[updated Mar. 2017 by FlyBase; FBrf0222196]
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003, pubmed:14628900). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias' (SCAs). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord; the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]
[SPINOCEREBELLAR ATAXIA 17; SCA17](https://omim.org/entry/607136)
[TATA BOX-BINDING PROTEIN; TBP](https://omim.org/entry/600075)
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. [From GeneReviews, Spinocerebellar Ataxia Type 17, pubmed:20301611, 2015.12.15]
SCA17 is an autosomal dominant neurologic disorder characterized by ataxia, pyramidal and extrapyramidal signs, cognitive impairments, psychosis, and seizures. Its clinical phenotype and inheritance pattern are similar to Huntington disease (HD; OMIM:143100). Individuals with normal TBP alleles have between 25 and 44 repeats, whereas SCA17 patients have between 47 and 63 repeats. Reduced penetrance is seen with 45 to 46 repeats (summary by Gao et al., 2008, pubmed:18043721). [From OMIM:607136, 2015.12.15]
This form of autosomal dominant spinocerebellar ataxia, SCA17 can be caused by heterozygous expansion of a trinucleotide repeat encoding glutamine (CAG or CAA) in TBP, the gene encoding the TATA box-binding protein. Rarely, SCA17 has been found to be caused by homozygous or compound heterozygous TBP repeat expansions. [From OMIM:607136, 2015.10.30]
Ortholog of human ITPR1, and ITPR3 (1 Drosophila to 2 human).
Dmel\Tbp shares 58% identity and 63% similarity with human TBP, and 54% identity and 62% similarity to human TBPL2.