Curation SCA6 CACNA1A

Gene CACNA1A

Disease SCA6

Inheritance AD

Score

12 + 6 = 18 / 18

Genetic + experimental = total

Classification

Definitive

Refuted

Moderate

Definitive

Last Updated 08/12/2025

Pubs Reviewed 5

Publication Span 28.25 years

Publication Interval 28.25 years

Curator(s) Macayla Weiner, Laurel Hiatt

Description

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant, late-onset, slowly progressive cerebellar ataxia caused by expansion of a CAG repeat in CACNA1A, encoding an expanded polyglutamine tract in the alpha1A/P/Q-type calcium-channel gene product/alpha1ACT. Expanded alleles were initially observed in unrelated ataxia cases and absent from controls, segregate or share disease haplotypes in families, and repeat-unit number influences age at onset and threshold interpretation. Functional evidence supports Purkinje-cell vulnerability and a toxic gain-of-function mechanism involving CACNA1A C-terminal/alpha1ACT biology, with rescue of model phenotypes by reducing IRES-driven alpha1ACTSCA6 translation.

All criTRia Curations Locus Page

Genetic evidence

Total: 12

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:39996131	6	Observational cohort of 2,768 individuals tested for CACNA1A CAG repeat units; results support SCA6 diagnosis at >=21 repeat units, with 19-20 repeat units interpreted as an intermediate range requiring opposite-allele and clinical context.
Collective Evidence	Segregation	PMID:15026782	1.5	In 12 Dutch SCA6 families, 8 shared a CACNA1A-region core haplotype between D19S1165 and D19S840 (3-3-6-22-3) that was absent from 80 control chromosomes; additional LD and genealogical data supported a founder haplotype.
Statistics	Case-control data	PMID:8988170	6	Expanded CACNA1A CAG alleles (21-27 repeats) were found in 8/133 unrelated ataxia index cases and in 0/475 ethnically matched non-ataxia controls, whose alleles ranged from 4-16 repeats (Fisher exact P < 1e-5).
Collective Evidence	Allele	PMID:39996131	2	Repeat-unit number refines pathogenic interpretation: family history positivity increased above 19 repeat units and plateaued at >=23; >=23 repeat units appeared sufficient for disease regardless of opposite allele, while 19-20 repeat units were intermediate and 21-22 repeat units were modified by opposite-allele length.

Experimental evidence

Total: 6

Per page

Category	Type	Citation	Score	Details
Function	Biochemical function	PMID:8988170	0.5	CACNA1A encodes the alpha1A/P-Q-type voltage-dependent calcium-channel subunit; the SCA6 CAG repeat lies in the open reading frame of several isoforms and is predicted to encode an expanded polyglutamine tract.
Function	Biochemical function	PMID:23331413	0.5	Secondary review: CACNA1A is the P/Q-type alpha1A calcium-channel gene for SCA6, and the SCA6 expansion encodes an expanded polyglutamine tract. The review also discusses RNAi-based post-transcriptional silencing as a therapeutic concept, not primary locus-specific data.
Function	Regulatory impact	PMID:8988170	1.5	Alternative CACNA1A isoforms were identified; GGCAG insertion/splicing can place the CAG repeat within an extended open reading frame, making the repeat polyglutamine-coding in specific isoforms.
Models	Non-human model organism	PMID:27412786	2	AAV9-mediated expression of CACNA1A IRES-driven alpha1ACT-Q33 in neonatal wild-type mice caused early-onset motor deficits, gait instability, Purkinje-cell degeneration, and approximately 50% Purkinje-cell loss.
Rescue	Rescue in non-human model organism	PMID:27412786	2	AAV9-miR-3191-5p reduced IRES-driven alpha1ACT-Q33 protein expression and rescued SCA6 mouse phenotypes, including Purkinje-cell degeneration, rotarod/open-field performance, and gait instability.

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