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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice.
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A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice.

机译：Cacng4的目标突变会加剧观星者（Cacng2）小鼠的尖峰波发作。

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摘要

The voltage-dependent calcium channel gamma4 subunit protein, CACNG4, is closely related to the gamma2 subunit, CACNG2. Both are expressed primarily in the brain and share 53% amino acid identity. The Cacng2 gene is disrupted in the stargazer mouse, with its distinctive phenotype including ataxia, frequent absence seizure episodes, and head elevation. A disruption within Cacng4 was engineered to assess its particular function. The homozygous Cacng4-targeted mutant mouse appeared normal with no ataxic gait or absence seizures, suggesting that other members of the gamma subunit family might functionally compensate for the absence of CACNG4. To test this hypothesis, the targeted Cacng4 mutation was combined with alleles of Cacng2. Absence seizures were observed in combination with the stargazer 3J mutation, which itself does not have seizures, and increased seizure activity was observed in combination with the waggler allele. Furthermore, within the corticothalamic loop, where absence seizures arise, CACNG4 expression is restricted to the thalamus. Our studies show that the CACNG4 protein has seizure suppressing activity, but this effect is revealed only when CACNG2 expression is also compromised, suggesting that CACNG subunits have in vivo overlapping functions.
机译：电压依赖性钙通道γ4亚基蛋白CACNG4与γ2亚基CACNG2密切相关。两者均主要在大脑中表达，并具有5​​3％的氨基酸同一性。 Cacng2基因在观星小鼠中被破坏，其独特的表型包括共济失调，频繁失神发作和头部抬高。设计了Cacng4中的中断来评估其特定功能。纯合Cacng4靶向突变小鼠看起来正常，没有共济失调步态或没有癫痫发作，表明γ亚基家族的其他成员可能会在功能上弥补CACNG4的缺乏。为了验证该假设，将靶向的Cacng4突变与Cacng2的等位基因结合。与本身没有癫痫发作的观星者3J突变相结合，观察到无癫痫发作，而与摇摆摆动的等位基因相结合，观察到癫痫发作活性增加。此外，在皮层丘脑环中，如果出现癫痫发作，CACNG4的表达仅限于丘脑。我们的研究表明，CACNG4蛋白具有抑制癫痫发作的活性，但是只有当CACNG2表达也受到损害时，才显示这种作用，这表明CACNG亚基具有体内重叠功能。

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