Fletcher C F, Lutz C M, O'Sullivan T N, Shaughnessy J D, Hawkes R, Frankel W N, Copeland N G, Jenkins N A
Mammalian Genetics Laboratory, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
Cell. 1996 Nov 15;87(4):607-17. doi: 10.1016/s0092-8674(00)81381-1.
Mutations at the mouse tottering (tg) locus cause a delayed-onset, recessive neurological disorder resulting in ataxia, motor seizures, and behavioral absence seizures resembling petit mal epilepsy in humans. A more severe allele, leaner (tg(la)), also shows a slow, selective degeneration of cerebellar neurons. By positional cloning, we have identified an alpha1A voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice. The alpha1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg(la) mice, providing evidence for regional differences in biological function of alpha1A channels. These studies define the first mutations in a mammalian central nervous system-specific voltage-sensitive calcium channel and identify the first gene involved in absence epilepsy.
小鼠蹒跚（tg）基因座的突变会导致一种迟发性隐性神经疾病，引发共济失调、运动性癫痫发作以及类似人类失神性癫痫的行为性失神发作。一个更为严重的等位基因，即瘦型（tg(la)），还表现出小脑神经元的缓慢、选择性退化。通过定位克隆，我们鉴定出了一个在tg和tg(la)小鼠中发生突变的α1A电压敏感性钙通道基因。α1A基因在中枢神经系统中广泛表达，在小脑中表达显著且均匀。α1A的表达并不反映在tg(la)小鼠中观察到的小脑退化的局部模式，这为α1A通道生物学功能的区域差异提供了证据。这些研究确定了哺乳动物中枢神经系统特异性电压敏感性钙通道中的首个突变，并鉴定出了首个与失神性癫痫相关的基因。
