Curation SCA3 ATXN3

Gene ATXN3

Disease SCA3

Inheritance AD

Score

12 + 5.5 = 17.5 / 18

Genetic + experimental = total

Classification

Definitive

Refuted

Moderate

Definitive

Last Updated 08/12/2025

Pubs Reviewed 9

Publication Span 29.5 years

Publication Interval 29.5 years

Curator(s) Macayla Weiner, Laurel Hiatt, Harriet Dashnow

Description

Spinocerebellar ataxia type 3 (SCA3/Machado-Joseph disease) is an autosomal dominant polyglutamine neurodegenerative disorder caused by a heterozygous CAG repeat expansion in ATXN3. The disorder is characterized by progressive cerebellar ataxia with variable pyramidal, extrapyramidal, peripheral motor neuron, ophthalmologic, and other neurologic features. Reported normal alleles are generally much shorter than pathogenic alleles, and multiple studies support a repeat-length effect, with larger expanded alleles associated with earlier age at onset and anticipation.

All criTRia Curations Locus Page

Genetic evidence

Total: 12

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:7573040	3	Four unrelated French families were studied; all showed expanded CAG repeats and the SCA3/MJD phenotype.
Singular Evidence	Probands	PMID:8619527	3	Thirty-four families with confirmed SCA3/MJD were clinically characterized, demonstrating broad phenotypic variability.
Collective Evidence	Allele	PMID:9040742 PMID:7573040	2	PMID 9040742 reports that in four Chinese MJD/SCA3 pedigrees, all 15 affected individuals had expanded ATXN3/MJD1 CAG alleles of 72-86 repeats versus 14-40 repeats in normal alleles, with a significant inverse correlation between expanded repeat length and age at onset and anticipation across generations. PMID 7573040 also found a significant negative correlation between expanded repeat length and age at onset in 28 individuals from three families of French descent.
Statistics	Case-control data	PMID:40178277 PMID:39921113 PMID:39731318	6	Available uploaded sources include molecularly confirmed SCA3 cohorts with comparison controls: 128 SCA3 patients and 125 controls with normal CAG-repeat ranges (pmid:40178277), 45 SCA3 patients and 44 controls (pmid:39921113), and 281 unrelated genetically confirmed SCA3 patients with 182 controls plus a 96-patient phenotyped cohort with expanded ATXN3 CAG alleles of 56-84 repeats (pmid:39731318). These studies provide patient-control cohort context but are not primary discovery case-control enrichment studies.

Experimental evidence

Total: 5.5

Per page

Category	Type	Citation	Score	Details
Function	Biochemical function	PMID:22133674	0.5	This study shows that ATXN3 is a deubiquitinating enzyme involved in ubiquitin-mediated proteostasis.
Function	Protein interaction	PMID:19811945	0.5	The study shows evidence of ATXN3 interaction, aggregation, and sequestration mechanisms.
Function	Regulatory impact	PMID:19811945	0.5	Evidence of altered transcriptional regulation and DNA-binding ability.
Models	Non-human model organism	PMID:17953484	4	Drosophila and C. elegans models both exhibit disease phenotypes and have been used to study disease mechanisms.

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