Xu Ruwei, Thomas Evan A, Jenkins Misty, Gazina Elena V, Chiu Cindy, Heron Sarah E, Mulley John C, Scheffer Ingrid E, Berkovic Samuel F, Petrou Steven
Howard Florey Institute, The University of Melbourne, Parkville, Victoria, 3010, Melbourne, Australia.
Mol Cell Neurosci. 2007 Jun;35(2):292-301. doi: 10.1016/j.mcn.2007.03.003. Epub 2007 Mar 13.
Seizure susceptibility is high in human infants compared to adults, presumably because of developmentally regulated changes in neural excitability. Benign familial neonatal-infantile seizures (BFNIS), characterized by both early onset and remission, are caused by mutations in the gene encoding a human sodium channel (NaV1.2). We analyzed neonatal and adult splice forms of NaV1.2 with a BFNIS mutation (L1563V) in human embryonic kidney cells. Computer modeling revealed that neonatal channels are less excitable than adult channels. Introduction of the mutation increased excitability in the neonatal channels to a level similar to adult channels. By contrast, the mutation did not affect the adult channel variant. This "adult-like" increased excitability is likely to be the mechanism underlying BFNIS in infants with this mutation. More generally, developmentally regulated NaV1.2 splicing may be one mechanism that counters the normally high excitability of neonatal neurons and helps to reduce seizure susceptibility in normal human infants.
与成年人相比，人类婴儿的癫痫易感性较高，这可能是由于神经兴奋性的发育调控变化所致。良性家族性新生儿 - 婴儿惊厥（BFNIS）的特征是起病早且缓解，它是由编码人类钠通道（NaV1.2）的基因突变引起的。我们在人胚肾细胞中分析了具有BFNIS突变（L1563V）的NaV1.2的新生儿和成人剪接形式。计算机建模显示，新生儿通道的兴奋性低于成人通道。引入该突变使新生儿通道的兴奋性增加到与成人通道相似的水平。相比之下，该突变不影响成人通道变体。这种“成人样”的兴奋性增加可能是具有该突变的婴儿中BFNIS的潜在机制。更一般地说，发育调控的NaV1.2剪接可能是一种机制，可对抗新生儿神经元通常较高的兴奋性，并有助于降低正常人类婴儿的癫痫易感性。
