Authors :
Yang yuling, PhD – Zhongshan Hospital, Fudan University; Wu Xiaoling, PhD – Zhongshan Hospital, Fudan University; Cai Yang, MD – Zhongshan Hospital, Fudan University; Ding Jing, PhD – Zhongshan Hospital, Fudan University; Wang Xin, PhD – Zhongshan Hospital, Fudan University
Rationale: Encoded by SCN2A, Nav1.2 is the major sodium channel during early neurodevelopment and remains to be abundantly expressed in mature neurons. The numerous studies have recognized the
pathogenic role of SCN2A variants in neurodevelopmental disorders including epileptic encephalopathy, autism spectrum disorder and mental retardation. Epilepsy caused by SCN2A mutation is commonly characterized by an early or infantile age of onset with poor prognosis. Although it has been shown that patients carrying SCN2A variants can also have late onset seizures, these patients often suffer from developmental regression or retardation. There is a paucity of studies indicating the role of SCN2A variants in genetic generalized epilepsy (GGE). The aim of this study was to determine the concerns of SCN2A variants with GGE.
Methods: Whole-exome sequencing was performed to identify the causative genes in the probands. By engineering variants into the adult isoform of Nav1.2, we compared electrophysiological properties of sodium channels containing wide-type or variant Nav1.2 subunits using whole-cell voltage clamp recordings in heterologous HEK-293T cells. Computational modeling was performed to simulate the effects of Nav1.2 variants on neuronal excitability in mature cortical pyramidal neurons.
Results: Two novel SCN2A mutations (E512K and N916S) associated with GGE were identified in two unrelated Chinese families. Both probands were diagnosed with GGE for the later age of onset, typical clinical episode, characterized generalized spike and wave discharges (GSWDs), normal development, and good response to anti-seizure medication. In addition, more interesting correlation between EEG abnormality and pathogenic mutation carrying was obvious and co-segregated in the two families, suggesting a critical role of Nav1.2 in modulating the electrical rhythm of human brain networks. Electrophysiological analysis demonstrated that the two mutations have opposite effects on the electrophysiological properties of Nav1.2. E512K induced gain of function of Nav1.2 because of premature activation, while N916S caused loss of function by a hyperpolarizing shift of voltage dependence of inactivation and slower recovery from inactivation. Computational modeling revealed that the E512K mutation led to hyperexcitation of cortical pyramidal neurons.
Conclusions: Our results indicated the involvement of SCN2A mutation in genetic generalized epilepsy and abnormal EEG. The functional characterization revealed that both gain and loss of function of Nav1.2 would disturb the balance between excitation and inhibition in the brain, thus resulting in abnormal EEG activity or even epilepsy.
Funding: None