TBP – Spinocerebellar Ataxia Type 17

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant neurodegenerative disorder caused by CAG/CAA repeat expansions in the TATA-binding protein gene (TBP). Clinically, SCA17 manifests with progressive cerebellar ataxia, cognitive impairment, chorea, dystonia and seizures, overlapping both Huntington-like and frontotemporal dementia phenotypes.

Genetic studies have established a pathological threshold of ≥43 CAG/CAA repeats, with full-penetrance alleles (≥50 repeats) and reduced-penetrance alleles (41–49 repeats).
In a cohort of 1,318 white SCA patients, 15 individuals from four families harbored expansions of 45–54 repeats ([PMID:12953269]) and exhibited variable ataxia and dementia. A series of case reports has described de novo expansions up to 55 repeats, homozygous intermediate expansions due to isodisomy, and asymptomatic carriers, illustrating both intergenerational instability and reduced penetrance ([PMID:12891385], [PMID:21710129]).

Segregation analyses demonstrate co-segregation of expanded alleles with disease in multiple pedigrees, although non-penetrance is observed in some carriers of 43–48 repeats within the same kindreds, indicating modifier effects and age-dependent expressivity.

At the molecular level, TBP polyglutamine expansions perturb transcription initiation by resisting normal TBP–TAF and TBP–TFIIB interactions, leading to widespread dysregulation of RNA polymerase II–dependent gene expression. Yeast and mammalian functional assays reveal that TBP variants alter promoter specificity and stability of the preinitiation complex, supporting a toxic gain-of-function mechanism associated with polyglutamine aggregation ([PMID:1586948], [PMID:9054459]).

Recent data identify digenic inheritance involving rare STUB1 variants that modulate disease penetrance in individuals carrying intermediate TBP expansions, redefining SCA17 as a monogenic dominant disorder for full repeats and a digenic TBP/STUB1 condition for intermediate ranges.

Conflicting evidence arises from population screens showing similar frequencies of 41–44 repeats in controls and patients, questioning the pathogenicity cutoff for low-range expansions and underscoring the need for longitudinal and neuropathological correlation ([PMID:26267067]).

In summary, SCA17 is definitively associated with TBP CAG/CAA repeat expansions in an autosomal dominant pattern, supported by robust genetic segregation and functional concordance. TBP testing is clinically useful for patients presenting with ataxia, cognitive decline or Huntington-like features, and should be integrated into differential diagnostic panels for adult-onset neurodegenerative disorders.

Key Take-home: TBP CAG/CAA expansions ≥43 repeats cause SCA17 with high clinical utility for genetic diagnosis in adult-onset cerebellar ataxia and neuropsychiatric syndromes.

References

• Annals of neurology • 2003 • Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). PMID:12953269
• European journal of human genetics • 2003 • SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6. PMID:12891385
• Neurological sciences • 2011 • Early-onset SCA17 with 43 TBP repeats: expanding the phenotype? PMID:21710129
• PloS one • 2015 • The Pathogenic Role of Low Range Repeats in SCA17. PMID:26267067
• Cell • 1992 • Variants of the TATA-binding protein can distinguish subsets of RNA polymerase I, II, and III promoters. PMID:1586948
• The Journal of biological chemistry • 1997 • Critical role of the second stirrup region of the TATA-binding protein for transcriptional activation both in yeast and human. PMID:9054459

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