PDF(Pubmed)
Abstract：
SCN2A encodes a voltage-gated sodium channel (NaV1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in SCN2A are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss-of-function variants typically being associated with neurodevelopmental delay and later-onset seizures, whereas gain-of-function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing SCN2A variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in SCN2A. Voltage-clamp studies of the variant expressed on adult and neonatal NaV1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss-of-function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage dependence of activation and an increase in the voltage dependence of inactivation. This finding of a predominantly loss-of-function effect was unexpected, as the infant\'s early epilepsy onset would have suggested a predominantly gain-of-function effect. This case illustrates that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.NEW & NOTEWORTHY Voltage-gated sodium channels play an important role in the central nervous system, mutations in which have been reported to be responsible for epilepsy. We report here an infant presenting with epilepsy of infancy with migrating focal seizures (EIMFS) in the neonatal period with a mosaic c.2635G>A, resulting in a p.Gly879Arg missense mutation on the SCN2A gene encoding NaV1.2 sodium channels. Biophysical characterization of this variant revealed a mixture of gain- and loss-of-function effects.
摘要：
SCN2A编码在整个中枢神经系统中主要在兴奋性神经元中表达的电压门控钠通道（NaV1.2）。SCN2A的致病变异与癫痫和神经发育障碍有关。已经描述了基因型-表型相关性，功能丧失变异通常与神经发育迟缓和迟发性癫痫发作有关，而功能获得变异更常导致早期婴儿发作癫痫。然而,大多数致病SCN2A变异体的真正电生理效应尚未被表征.我们报告了一名在新生儿期出现局灶性癫痫发作的婴儿。她被发现有一个马赛克c.2635G>A，SCN2A中的p.Gly879Arg变体。在成人和新生儿NaV1.2同种型上表达的变体的电压钳研究表明，功能的增加和丧失是混合的，主要具有功能丧失效应，细胞表面表达和电流密度降低。其他小的电生理改变包括激活的电压依赖性降低和失活的电压依赖性增加。这种主要的功能丧失效应的发现是出乎意料的，因为婴儿的早期癫痫发作表明主要是功能获得效应。这种情况说明我们对基因型-表型相关性的理解仍然有限，并且突出了SCN2A变体的潜在电生理效应的复杂性。电压门控钠通道在中枢神经系统中起着重要作用，据报道，这些突变是导致癫痫的原因。我们在这里报告了一名婴儿，在新生儿期出现癫痫伴转移性局灶性癫痫发作（EIMFS），马赛克c.2635G>A，在编码NaV1.2钠通道的SCN2A基因上产生p.Gly879Arg错义突变。该变体的生物物理表征揭示了功能增益和功能丧失效应的混合。
