SCA6 is caused by moderate CAG expansion in the alpha1A-voltage- dependent calcium channel gene

Abstract

Recently, moderate (CAG)>20 repeat expansions in the alpha1A-voltage-dependent calcium channel gene (CACNL1A4) have been identified in a previously unmapped type of SCA which has been named SCA6. We investigated the (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadic ataxia and in 46 German families with dominantly inherited SCA which do not harbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)n expansion was identified in 32 patients most frequently with late manifestation of the disease. The (CAG)n stretch of the affected allele varied between 22 and 28 trinucleotide units and is therefore the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)n repeat length is inversely correlated with the age at onset. In 11 parental transmissions of the expanded allele no repeat instability has been observed. Repeat instability was also not found for the normal allele investigating 431 meioses in the CEPH families. Analyzing 248 apparently healthy octogenerians revealed one allele of 18 repeats which is the longest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutation causes the disease in approximately 10% of autosomal dominant SCA in Germany. Most importantly, the trinucleotide expansion was observed in four ataxia patients without obvious family history of the disease which necessitates a search for the SCA6 (CAG)n expansion even in sporadic patients.

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

“…36,93 Small triplet expansions of the intragenic CAG repeat ranging from 21 to 30 repeat units were observed in patients with autosomal dominant cerebellar ataxia (SCA6), [93][94][95] whereas normal chromosomes displayed 4-20 repeats. 36,[93][94][95][96] The CAG repeat length is inversely correlated with age at onset. [94][95][96] Anticipation of the disease was observed clinically 94 but no detectable intergenerational allele size change was seen in contrast to other disease-causing repeats (eg in other SCAs and Huntington disease).…”

“…36,[93][94][95][96] The CAG repeat length is inversely correlated with age at onset. [94][95][96] Anticipation of the disease was observed clinically 94 but no detectable intergenerational allele size change was seen in contrast to other disease-causing repeats (eg in other SCAs and Huntington disease). The occurrence of the SCA6 mutation was estimated to be 10% of SCA patients in Germany, 95 whereas in Japan SCA6 comprised 30% of the examined ataxia patients and one homozygous case was found suggesting a founder effect.…”

Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?

“…Recently, mild CAG expansions within the ␣1-calcium channel gene (21-27 repeats, with 4-17 repeats in normal alleles) were described in a subset of patients with spinocerebellar ataxia (SCA), patients having the expansion (found in eight of 266 patient-chromosomes) being given the diagnosis of SCA-6; 5 replicative studies now show normal alleles with up to 20 repeats, producing a continuous distribution of normal and pathogenic allele lengths. [6][7][8] This protein has a well-defined function within neurons, and, although this has yet to be tested, electrophysiological strategies should easily discern even subtle changes in channel function resulting from polyglutamine repeats longer by even one glutamine.…”

“…This mechanism is reminiscent of the continuous distribution of alleles for the ␣1-calcium channel gene involved in SCA-6. [5][6][7][8] If a change in length by a single glutamine in an array can result in a perceptible change in channel function, one might expect a continuous gradation of effects of polyglutamine length on the channel's biophysical properties. The resulting consequences for neuronal excitability, and therefore disease susceptibility, will depend on the interplay between the complex ensemble of channel types and many other cellular regulators.…”

Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan

“…Even in patients with spinocerebellar ataxia type 6 (SCA6), who have only a moderate increase in the CAG triplet repeat numbers in the ␣1A-calcium channel gene, [11][12][13] and a continuous distribution of CAG triplet repeat numbers between normal controls and affected patients, 14 there is no overlap of the triplet repeat numbers between patients and controls. In addition, most of the trinucleotide-associated neurodegenerative diseases are dominant diseases and show high penetrance.…”