CACNA1G – Spinocerebellar Ataxia Type 42

Spinocerebellar ataxia type 42 (SCA42) is an autosomal-dominant neurodegenerative disorder caused by heterozygous missense variants in the CACNA1G gene, which encodes the T-type voltage-gated calcium channel CaV3.1. The recurrent c.5144G>A (p.Arg1715His) change was first identified by linkage and exome sequencing in a large French family and subsequently found in a Japanese pedigree (2/479 screened index cases) ([PMID:26456284])( [PMID:31229688]).

Clinical Validity (Strong)

Multiple unrelated families, including a French kindred with segregation in 19 affected relatives and at least five additional families worldwide, harbor pathogenic CACNA1G missense variants. Independent reports describe >20 probands with SCA42 or overlapping cerebellar syndromes across diverse ancestries, with concordant clinical and pathological features (Purkinje cell loss, cerebellar atrophy).

Genetic Evidence (Strong)

Inheritance is autosomal dominant. Segregation analysis in the French cohort demonstrated co-segregation of p.Arg1715His in 19 affected relatives. Additional de novo and familial missense variants include c.2881G>A (p.Ala961Thr), c.4591A>G (p.Met1531Val), c.3835G>A (p.Asp1279Asn), and c.4721T>A (p.Met1574Lys), reported in both adult-onset SCA42 and infantile-onset syndromic cerebellar ataxia ([PMID:31836334])( [PMID:30200108]).

Functional Evidence (Strong)

A knock-in mouse model carrying the homologous Cacna1g p.Arg1723His mutation develops progressive ataxia from 11 weeks and Purkinje cell degeneration by 50 weeks, mirroring human pathology ([PMID:31229688]). Electrophysiology in HEK293T cells shows a positive shift in activation and altered rebound firing for p.Arg1715His ([PMID:26456284]). Importantly, zonisamide restores normal voltage dependence in mutant channels and ameliorates head tremor in an SCA42 patient ([PMID:33243296]).

Conflicting Evidence

No studies to date dispute the pathogenicity of CACNA1G missense variants in SCA42. Phenotypic variability is noted, but all pathogenic alleles impair CaV3.1 gating.

Integration & Conclusion

Heterozygous CACNA1G missense variants cause SCA42 via gain-of-function effects on T-type Ca²⁺ channel activation, leading to cerebellar dysfunction and Purkinje cell loss. Genetic, segregation, and robust in vivo and in vitro functional data support a strong gene-disease association. CACNA1G sequencing should be included in diagnostic panels for dominant cerebellar ataxia and related neurodevelopmental syndromes.

Key Take-home: Strong evidence links autosomal-dominant CACNA1G missense variants to SCA42, with actionable insights from functional rescue by zonisamide.

References

• Neurobiology of disease • 2019 • Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42. PMID:31229688
• American journal of human genetics • 2015 • A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. PMID:26456284
• Pediatric neurology • 2020 • Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations. PMID:31836334
• Molecular brain • 2020 • Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel CaV3.1 caused by a mutation responsible for spinocerebellar ataxia. PMID:33243296
• Medicine • 2018 • A case of a novel CACNA1G mutation from a Chinese family with SCA42: A case report and literature review. PMID:30200108

Evidence Based Scoring (AI generated)