X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3.
X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3.
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X连锁新生儿癫痫性脑病与GRIA3中功能获得性变异p.R660T相关
DOI：
10.1371/journal.pgen.1009608
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发表时间：
2021-06
期刊：
影响因子：
4.5
通讯作者：
Shi YS
中科院分区：
文献类型：
--
作者：
Sun JH;Chen J;Ayala Valenzuela FE;Brown C;Masser-Frye D;Jones M;Romero LP;Rinaldi B;Li WL;Li QQ;Wu D;Gerard B;Thorpe E;Bayat A;Shi YS
X连锁的GRIA3基因编码AMPA型谷氨酸受体的GLUA3亚单位。该基因的致病变异以前在神经发育疾病中被报道过，主要发生在男性患者中，但很少发生在女性患者中。在这里，我们报告了在一名患有严重癫痫和全球发育迟缓的1岁女性患者中发现的GRIA3(C.1979G>；C；p.R660T)新生致病错义变异。与野生型(Wt)GLUA3受体相比，外源表达的GLUA3_R660T在人胚胎肾(HEK)细胞中表现出较慢的失敏和失活动力学。在突变体中观察到大量的非脱敏电流，但在长期暴露于谷氨酸的wt GLUA3中没有观察到。当GLUA2与GLUA2共表达时，GLUA2/A3_R660T的衰减动力学也同样减慢，且稳态电流不敏感。在培养的小脑颗粒神经元中，R660T转基因细胞的微小兴奋性突触后电流(MEPSCs)明显慢于表达wt GLUA3的细胞。宫内电穿孔过表达时，表达R660T突变体的神经元中诱发的EPSCs和mEPSCs较表达wt GLUA3的神经元慢。因此，我们的研究提供了功能证据，表明GRIA3的功能获得(GOF)变异可能通过增强突触传递而导致女性癫痫脑病和全球发育延迟。
The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.
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影响因子：
5.7
作者：
Anggono V;Huganir RL
通讯作者：
Huganir RL
DOI：
10.1126/science.aad3873
发表时间：
2016-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Herguedas B;García-Nafría J;Cais O;Fernández-Leiro R;Krieger J;Ho H;Greger IH
通讯作者：
Greger IH
影响因子：
7
作者：
Eberle, Michael A.;Fritzilas, Epameinondas;Bentley, David R.
通讯作者：
Bentley, David R.
影响因子：
16.2
作者：
Jackson AC;Nicoll RA
通讯作者：
Nicoll RA
影响因子：
21.1
作者：
Brodie MJ;Besag F;Ettinger AB;Mula M;Gobbi G;Comai S;Aldenkamp AP;Steinhoff BJ
通讯作者：
Steinhoff BJ