Drosophila as a Model for Epilepsy: bss Is a Gain-of-Function Mutation in the Para Sodium Channel Gene That Leads to Seizures
Drosophila as a Model for Epilepsy: bss Is a Gain-of-Function Mutation in the Para Sodium Channel Gene That Leads to Seizures
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DOI：
10.1534/genetics.110.123299
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发表时间：
2011-02-01
期刊：
影响因子：
3.3
通讯作者：
Tanouye, Mark A.
中科院分区：
文献类型：
--
作者：
Parker, Louise;Padilla, Miguel;Tanouye, Mark A.
我们报道了一种表现出类似于果蝇行为的突变体bang senseless（bang）的鉴定，该突变体是麻痹性（帕拉）电压门控Na（+）（Na（V））通道基因的等位基因。突变体比正常果蝇更容易发作，因为它们的发作阈值较低。该表型是由于一个错义突变的一段先前涉及失活，称为“桨状基序”的Na（V）的第四同源结构域。异源表达的cDNA含有的的cDNAs（I）损伤，随后的电生理学，显示突变通道显示出改变的电压依赖性的失活相比，野生型。在果蝇中，bang敏感突变体中最严重的是bang的表型，可以通过抗癫痫药物治疗来改善，但不能抑制。因此，BSS相关癫痫发作类似于由人Na（V）SCN 1A突变引起的抗癫痫性癫痫发作，例如婴儿严重肌阵挛性癫痫或伴有全身强直阵挛性癫痫发作的难治性儿童癫痫。
We report the identification of bang senseless (bss), a Drosophila melanogaster mutant exhibiting seizure-like behaviors, as an allele of the paralytic (para) voltage-gated Na(+) (Na(V)) channel gene. Mutants are more prone to seizure episodes than normal flies because of a lowered seizure threshold. The bss phenotypes are due to a missense mutation in a segment previously implicated in inactivation, termed the "paddle motif" of the Na(V) fourth homology domain. Heterologous expression of cDNAs containing the bss(I) lesion, followed by electrophysiology, shows that mutant channels display altered voltage dependence of inactivation compared to wild type. The phenotypes of bss are the most severe of the bang-sensitive mutants in Drosophila and can be ameliorated, but not suppressed, by treatment with anti-epileptic drugs. As such, bss-associated seizures resemble those of pharmacologically resistant epilepsies caused by mutation of the human Na(V) SCN1A, such as severe myoclonic epilepsy in infants or intractable childhood epilepsy with generalized tonic-clonic seizures.