Jouvenceau A, Eunson L H, Spauschus A, Ramesh V, Zuberi S M, Kullmann D M, Hanna M G
University Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, WC1N 3BG, London, UK.
Lancet. 2001 Sep 8;358(9284):801-7. doi: 10.1016/S0140-6736(01)05971-2.
The genetic basis of most common forms of human paroxysmal disorders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca(2+)) channel. We aimed to determine whether the P/Q-type Ca(2+) channel is associated with both epilepsy and episodic ataxia type 2 in human beings.
We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca(2+) channel (CACNA1A) on chromosome 19. We then introduced the newly identified heterozygous mutation into the full-length rabbit cDNA and did detailed electrophysiological expression studies of mutant and wild type Ca(2+) channels.
We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop) resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca(2+) channel. Expression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect.
Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.
大多数常见的人类中枢神经系统阵发性疾病，如癫痫，其遗传基础仍未明确。几种失神癫痫的动物模型通常伴有共济失调，是由脑P/Q型电压门控钙（Ca(2+)）通道的突变引起的。我们旨在确定P/Q型Ca(2+)通道是否与人类癫痫和2型发作性共济失调有关。
我们鉴定出一名11岁男孩，其具有复杂的表型，包括原发性全身性癫痫、发作性和进行性共济失调以及轻度学习困难。我们对位于19号染色体上的电压门控P/Q型Ca(2+)通道（CACNA1A）编码基因的整个编码区进行了测序。然后我们将新鉴定的杂合突变引入全长兔cDNA，并对突变型和野生型Ca(2+)通道进行了详细的电生理表达研究。
我们在CACNA1A中鉴定出一个先前未描述的杂合点突变（C5733T）。该突变引入了一个提前终止密码子（R1820stop），导致该Ca(2+)通道孔形成亚基的C末端区域完全缺失。表达研究提供了直接证据，表明该突变损害了Ca(2+)通道功能。突变体/野生型共表达研究表明存在显性负效应。
人类失神癫痫可能与脑P/Q型电压门控Ca(2+)通道功能障碍有关。该患者的表型与小鼠失神癫痫模型有显著相似之处。
