A Missense Mutation in a Highly Conserved Alternate Exon of Dynamin-1 Causes Epilepsy in Fitful Mice
A Missense Mutation in a Highly Conserved Alternate Exon of Dynamin-1 Causes Epilepsy in Fitful Mice
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DOI：
10.1371/journal.pgen.1001046
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发表时间：
2010-08-01
期刊：
影响因子：
4.5
通讯作者：
Frankel, Wayne N.
中科院分区：
文献类型：
--
作者：
Boumil, Rebecca M.;Letts, Verity A.;Frankel, Wayne N.
发动蛋白-1（Dnm 1）编码一个大的多聚体GTdR，它是神经元活动依赖性膜再循环所必需的，包括突触囊泡内吞作用。一种新的自发性Dnm 1突变的杂合子小鼠--间歇性发作--经历反复发作，而纯合子小鼠除了严重的共济失调和神经感觉缺陷外，还具有更严重的衰弱性，通常是致命的癫痫发作。Fitful是定义DNM 1a亚型的外显子中的错义突变，保留编码DNM 1b的可变剪接外显子完整。相应的替代转录本的表达是发育调节的，DNM 1b的表达在早期神经元发育过程中最高，DNM 1a的表达在出生后随着突触成熟而增加。突变体DNM 1a不能有效地自组装成已知为适当发动蛋白功能所必需的高阶复合物，并且它还干扰细胞培养物中的内吞再循环。在小鼠中，这种突变导致突触传递缺陷，其特征是在一连串刺激后从抑郁中恢复较慢。DNM 1a和DNM 1b亚型对在脊椎动物进化中高度保守，而无脊椎动物只有一种亚型。我们推测，DNM 1的更专门的形式的出现可能是重要的生物体与复杂的神经元功能。
Dynamin-1 (Dnm1) encodes a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Mice heterozygous for a novel spontaneous Dnm1 mutation-fitful-experience recurrent seizures, and homozygotes have more debilitating, often lethal seizures in addition to severe ataxia and neurosensory deficits. Fitful is a missense mutation in an exon that defines the DNM1a isoform, leaving intact the alternatively spliced exon that encodes DNM1b. The expression of the corresponding alternate transcripts is developmentally regulated, with DNM1b expression highest during early neuronal development and DNM1a expression increasing postnatally with synaptic maturation. Mutant DNM1a does not efficiently self-assemble into higher order complexes known to be necessary for proper dynamin function, and it also interferes with endocytic recycling in cell culture. In mice, the mutation results in defective synaptic transmission characterized by a slower recovery from depression after trains of stimulation. The DNM1a and DNM1b isoform pair is highly conserved in vertebrate evolution, whereas invertebrates have only one isoform. We speculate that the emergence of more specialized forms of DNM1 may be important in organisms with complex neuronal function.