MRC Centre for Neuromuscular Diseases, Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, UK.
J Physiol. 2010 Jun 1;588(Pt 11):1905-13. doi: 10.1113/jphysiol.2009.186437. Epub 2010 Feb 15.
Mutations in CACNA1A, which encodes the principal subunit of the P/Q calcium channel, underlie episodic ataxia type 2 (EA2). In addition, some patients with episodic ataxia complicated by epilepsy have been shown to harbour CACNA1A mutations, raising the possibility that P/Q channel dysfunction may be linked to human epilepsy. We undertook a review of all published CACNA1A EA2 cases and this showed that 7% have epilepsy--representing a sevenfold increased epilepsy risk compared to the background population risk (P<0.001). We also studied a series of 17 individuals with episodic ataxia accompanied by epilepsy and/or clearly epileptiform electroencephalograms (EEGs). We screened the entire coding region of CACNA1A for point mutations and rearrangements to determine if genetic variation in the gene is associated with the epilepsy phenotype, and measured the functional impact of all missense variations on heterologously expressed P/Q channels. We identified two large scale deletions and two new missense mutations in CACNA1A. When expressed, L621R had little detectable effect on P/Q channel function, while the other missense change, G540R, caused an approximately 30% reduction in current density. In nine patients we also identified the previously reported non-synonymous coding variants (E921D and E993V) which also resulted in impairment of P/Q channel function. Taken together, 12 of the 17 patients have genetic changes which decrease P/Q channel function. We conclude that variants in the coding region of CACNA1A that confer a loss of P/Q-type channel function are associated with episodic ataxia and epilepsy. Our data suggest that functional stratification of all variants, including common polymorphisms, rare variants and novel mutations, may provide new insights into the mechanisms of channelopathies.
CACNA1A 基因突变是 2 型发作性共济失调（EA2）的主要致病原因，该基因编码 P/Q 型钙通道的主要亚基。此外，一些伴有癫痫发作的发作性共济失调患者已被证明存在 CACNA1A 基因突变，这提示 P/Q 通道功能障碍可能与人类癫痫有关。我们对所有已发表的 CACNA1A EA2 病例进行了回顾性分析，结果显示 7%的患者患有癫痫——与背景人群的癫痫风险相比增加了 7 倍（P<0.001）。我们还研究了一系列 17 例伴有癫痫发作和/或明显癫痫样脑电图（EEG）的发作性共济失调患者。我们对 CACNA1A 的整个编码区进行了点突变和重排筛查，以确定基因中的遗传变异是否与癫痫表型相关，并测量了所有错义变异对异源表达 P/Q 通道的功能影响。我们在 CACNA1A 中发现了两个大的缺失和两个新的错义突变。当表达时，L621R 对 P/Q 通道功能几乎没有可检测到的影响，而另一个错义变化 G540R 导致电流密度降低约 30%。在 9 例患者中，我们还鉴定了先前报道的非 synonymous 编码变异（E921D 和 E993V），这些变异也导致 P/Q 通道功能受损。总的来说，17 例患者中有 12 例存在降低 P/Q 通道功能的遗传变化。我们得出结论，CACNA1A 编码区的变异导致 P/Q 型通道功能丧失与发作性共济失调和癫痫有关。我们的数据表明，对所有变异（包括常见多态性、罕见变异和新突变）进行功能分层，可能为通道病的发病机制提供新的见解。
