氮透酶调节因子样蛋白3基因(nitrogen permease regulator like protein 3,NPRL3)是GATOR1复合体[GTPase-activating protein(GAP)activity towards Rags 1 complex]基因的一个亚单位,是哺乳动物雷帕霉素靶蛋白复合体1(mammalian target...氮透酶调节因子样蛋白3基因(nitrogen permease regulator like protein 3,NPRL3)是GATOR1复合体[GTPase-activating protein(GAP)activity towards Rags 1 complex]基因的一个亚单位,是哺乳动物雷帕霉素靶蛋白复合体1(mammalian target of rapamycin complex 1,mTORC1)上游的负性调控因子,NPRL 3基因的致病变异可导致GATOR1复合体功能丧失,从而异常增强mTORC1信号通路的活性,与局灶性癫痫高度相关,可伴或不伴局灶性皮层发育不良^([1,2])。展开更多
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.1514dup ...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.1514dup C and 6,706-bp genomic DNA(g DNA) 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 m TOR 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 m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 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.展开更多
文摘氮透酶调节因子样蛋白3基因(nitrogen permease regulator like protein 3,NPRL3)是GATOR1复合体[GTPase-activating protein(GAP)activity towards Rags 1 complex]基因的一个亚单位,是哺乳动物雷帕霉素靶蛋白复合体1(mammalian target of rapamycin complex 1,mTORC1)上游的负性调控因子,NPRL 3基因的致病变异可导致GATOR1复合体功能丧失,从而异常增强mTORC1信号通路的活性,与局灶性癫痫高度相关,可伴或不伴局灶性皮层发育不良^([1,2])。
基金supported by the National Natural Science Foundation of China (32270663, 31871262, U20A20355,32022035)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Ministry of Science and Technology of China STI2030-Major Projects (2021ZD0203202)。
文摘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.1514dup C and 6,706-bp genomic DNA(g DNA) 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 m TOR 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 m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 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.
