SCA6_CACNA1A
- Gene
- CACNA1A
- Disease
- SCA6
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 18
- Publications Reviewed
- 5
- Publication Span
- 28.25 years
- Last Updated
- 08/12/2025
- 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.
Genetic evidence
Total: 12
| 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
| 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. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.