Curation SCA51 THAP11

Gene THAP11

Disease SCA51

Inheritance AD

Score

10 + 3 = 13 / 18

Genetic + experimental = total

Classification

Definitive

Refuted

Moderate

Definitive

Last Updated 08/18/2025

Pubs Reviewed 4

Publication Span 21.16 years

Publication Interval 21.16 years

Curator(s) Macayla Weiner, Laurel Hiatt

Description

Autosomal dominant spinocerebellar ataxia 51 (SCA51) is associated with an exonic CAG/polyglutamine repeat expansion in THAP11. Reported SCA-associated alleles include expanded THAP11 repeats in the pathogenic range of approximately 45-100 repeats, with affected Chinese families showing reduced CAA interruptions and long pure CAG tracts that correlate with earlier onset and greater ataxia severity. Population-scale studies indicate that THAP11 expansions are rare and that repeat structure varies by ancestry, while functional studies support polyQ length-dependent THAP11 aggregation, altered transcription-related interactions, and cellular toxicity.

All criTRia Curations Locus Page

Genetic evidence

Total: 10

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:39651830 PMID:37148549	4.5	PMID 37148549: two unrelated Chinese SCA pedigrees with THAP11 CAG expansions, including a five-generation family and a second family. PMID 39651830: population-scale follow-up identified three UK Biobank individuals with neurological diagnoses and THAP11 expansions ≥ 45 repeats, including one hereditary ataxia case; curator review is needed because that ataxia case also carried a CACNA1A/SCA6 expansion.
Collective Evidence	Allele	PMID:39651830	2	PMID 39651830: THAP11 expansions ≥ 45 repeats were rare across Genomics England, UCL IoN, and UK Biobank datasets; expanded alleles in this study typically had 6 CAA interruptions and short 3′ uninterrupted CAG tracts (9-10 repeats), supporting population-level repeat-size/structure assessment rather than direct SCA-specific allele severity.
Collective Evidence	Computational	PMID:15368101 PMID:39651830 PMID:37148549	2	PMID 15368101: THAP11 is a polymorphic brain-expressed CAG/polyQ locus and folding simulations predicted increased unfolding/aggregation risk with longer polyQ tracts. PMID 37148549: predicted mutant THAP11 structures [(CAG)45/(CAG)100] showed altered polyQ/random-coil organization and potential protein-binding changes compared with shorter alleles. PMID 39651830: population-scale repeat-structure analysis showed ancestry-related differences in CAA interruptions and 3′ CAG tract architecture.
Collective Evidence	Segregation	PMID:37148549	1.5	PMID 37148549: THAP11 CAG expansions cosegregated with ataxic or preataxic status in family 1, and linkage analysis identified the 16q22.1 region containing THAP11 with maximum LOD score 3.994.

Experimental evidence

Total: 3

Per page

Category	Type	Citation	Score	Details
Function	Biochemical function	PMID:24677642	0.5	PMID 24677642: THAP11 is a transcription-associated nuclear protein; expanded THAP11(38Q) suppressed CRE-mediated transcriptional activity more strongly than THAP11(29Q) in PC12 cells.
Function	Protein interaction	PMID:24677642	0.5	PMID 24677642: co-immunoprecipitation in PC12 cells showed expanded THAP11(38Q), but not THAP11(29Q), recruited TBP, CBP, and HSP70; PCBP1 interacted with both forms.
Functional Alteration	Non-patient cells	PMID:24677642	1	Functional studies using PC12 cells, COS-7 cells, and neuronal/primary neuron cell models expressing THAP11 polyQ constructs. These experiments support THAP11 polyQ length-dependent aggregation, cellular toxicity, G0/G1 arrest, and altered transcription-related effects.
Functional Alteration	Non-patient cells	PMID:37148549	1	PMID 37148549: Neuro-2a cells expressing expanded THAP11-(CAG)54 or THAP11-(CAG)100 showed increased intracellular/cytoplasmic aggregation and reduced viability compared with THAP11-(CAG)29.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.