Elsevier

Brain Research Bulletin

Volume 56, Issues 3–4, 1 November 2001, Pages 227-231
Brain Research Bulletin

Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder?

https://doi.org/10.1016/S0361-9230(01)00574-3Get rights and content

Abstract

Spinocerebellar ataxia type 6 (SCA6) is due to small expansions of a CAG repeat at the 3′ end of the CACNA1A gene, coding for the α1A subunit of voltage-gated calcium channels type P/Q, expressed in the cerebellar Purkinje and granule cells. It is one of three allelic disorders, the other two being episodic ataxia type 2 (EA2), due mostly to protein truncating mutations, and familial hemiplegic migraine, associated with missense mutations. The latter disorders, due to point mutations altering the P/Q channel activity, clearly belong to the group of channelopathies. For SCA6, due to CAGn expansions, a toxic gain of function might, instead, be envisaged homologous to that of glutamine repeat disorders. A comparison between SCA6 and EA2 phenotypes performed on available literature data, shows that the clinical features of the two disorders are widely overlapping and that the differences could be accounted for with the older age of patients in the SCA6 group. A similar phenotype in the two disorders could imply the same pathogenic process. Functional analyses on cells expressing the protein with an expanded polyglutamine stretch have shown, in fact, an altered channel activity. In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders.

Introduction

Spinocerebellar ataxia type 6 (SCA6) is one of three allelic autosomal dominant disorders due to mutations of the CACNA1A gene, located on chromosome 19p13. The gene codes for the α1A subunit of voltage-gated calcium channels type P/Q, expressed throughout the brain and particularly in the cerebellar Purkinje and granule cells 41, 43. These channels are multimeric structures playing a prominent role in controlling neurotransmitter release in many synapses [5]. The subunit has four homologous domains (I–IV), each containing six hydrophobic transmembrane segments, S1–S6 (Fig. 1), and intracytoplasmic N- and C-terminal tails. A polymorphic polyglutamine sequence, coded by a CAGn repeat, is embedded in the C-terminal tail. The protein is the pore-forming subunit of the channels and is linked to other regulatory subunits. The CACNA1A transcript of approximately 9.8 kb [30], undergoes a considerable variety of alternative splicing, producing at least six isoforms, in only some of which the CAG repeat is translated and expressed as a polyglutamine sequence at the protein level [47].

SCA6 is associated with small expansions of this repeat [47], while other two allelic disorders are due to point mutations: Episodic ataxia type 2 (EA2), mostly but not exclusively, to protein truncating mutations 3, 7, 30, 45 and familial hemiplegic migraine (FHM) to missense mutations 4, 30. Normal CAG alleles of the CACNA1A gene range from 4 to 18 units 36, 37, 47. Expanded alleles range from 19 to 30 repeats 19, 22, 27, 36, 37, although evidence for the pathogenicity of 19 CAG allele is controversial [15]. In any case, the size of SCA6 expansions is well within the normal range for other polyglutamine disorders (SCA1-7, Huntington’s disease, spinal bulbar muscular atrophy, dentato-rubro-pallido-luysian atrophy). A complete sequence analysis of the gene coding region in a SCA6 patient excluded the presence of other detectable mutations [19]. Patients homozygous for the polyglutamine expansion show an earlier onset than heterozygotes and a more rapid course 10, 23, 26, 39. The size of SCA6 expanded alleles is more stable than that of other repeat expansion disorders, as expected on the basis of its relatively low number of units. No variation is usually observed in families over successive generations, and no mosaicism is apparent in cells from different parts of the brain [16] or in sperms [36]. However, some degree of meiotic instability should be assumed because in two families an intergenerational jump of the expanded allele size has been reported 19, 26.

Section snippets

Clinical features

The clinical picture of SCA6 has first been described by [47] as a late onset, slowly progressive cerebellar ataxia with nystagmus and dysarthria, brain stem involvement, vibratory and proprioceptive sensory loss, and an insidious onset characterised by ‘wooziness’ and momentary imbalance. The permanent and progressive character of the cerebellar deficit, the coexisting brainstem and sensory involvement led these authors to consider SCA6 as a disorder distinct from EA2, which was thought,

Pathogenesis

From a functional point of view the α1A subunit with an expansion of the polyglutamine tract may act either by altering the P/Q channel activity, or by acquiring a toxic gain of function as hypothesised for other polyglutamine disorders (see e.g., [31]). All functional evidence so far available points towards the first hypothesis. Matsuyama et al. [28] have shown in HEK293 cells, expressing rabbit α1A subunit with an expanded polyglutamine stretch and coexpressing auxiliary subunits α2δ and β4,

Conclusions

SCA6 differs from other disorders due to the expansion of a CAG repeat in many respects. In the latter diseases, the unstable expanded CAG stretch, located within the coding regions of their respective genes, typically has a number of units that ranges from 35 to over 100, while in the former the stable expanded alleles are much smaller. The gene products are nuclear or cytoplasmic rather than membrane proteins, to which the expanded polyglutamine stretch confers a gain of function, as shown,

Acknowledgements

Work supported by Telethon-Italia grant E847.

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