Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, 430074, China.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Sci China Life Sci. 2023 Sep;66(9):2152-2166. doi: 10.1007/s11427-022-2313-1. Epub 2023 Apr 12.
Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study, three novel mutations in NPRL3 (nitrogen permease regulator-like 3), c.937_945del, c.1514dupC and 6,706-bp genomic DNA (gDNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing (WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of mTOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced mTOR signaling in cultured cells, possibly due to impaired inhibition of mTORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.
局灶性癫痫占所有癫痫形式的 60%，但其发病机制尚不清楚。在这项研究中，通过连锁分析、全外显子组测序（WES）和 Sanger 测序，在三个局灶性癫痫家系中鉴定出 NPRL3（氮渗透调节因子样 3）的三个新突变，c.937_945del、c.1514dupC 和 6,706-bp 基因组 DNA（gDNA）缺失。NPRL3 蛋白是 GATOR1 复合物的一个组成部分，是 mTOR 信号的主要抑制剂。这些突变导致 NPRL3 蛋白截短，并阻碍 NPRL3 与 GATOR1 的另一个组成部分 DEPDC5 的结合。因此，突变蛋白增强了培养细胞中的 mTOR 信号，可能是由于 GATOR1 对 mTORC1 的抑制作用受损。果蝇中 nprl3 的敲低导致癫痫样行为和异常突触发育。总之，这些发现扩展了 NPRL3 相关局灶性癫痫的基因型谱，并进一步阐明了 NPRL3 突变如何导致癫痫。
