A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: Functional characterization and targeted treatment.
A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: Functional characterization and targeted treatment.
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DOI：
10.1111/epi.17419
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发表时间：
2022-12
期刊：
影响因子：
5.6
通讯作者：
Farrant, Mark
中科院分区：
文献类型：
--
作者：
Coombs, Ian D.;Ziobro, Julie;Krotov, Volodymyr;Surtees, Taryn-Leigh;Cull-Candy, Stuart G.;Farrant, Mark
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPAR）是由GluA 1 - 4亚基组合形成的配体门控阳离子通道。GRIA 1 -4的致病性变体已在患有发育迟缓、智力残疾、自闭症谱系障碍和癫痫发作的患者中描述，其中GRIA 2变体通常导致AMPAR功能丧失。在这里，我们确定了一个新的，杂合从头致病错义突变GRIA 2（c.1928 C>T，p.A643V，NM_001083619. 1）在1岁的男孩癫痫，发育迟缓，并未能茁壮成长。我们进行了膜片钳记录，以比较HEK 293细胞中表达的变体和野生型受体的功能和药理学特性，有和没有跨膜AMPAR调节蛋白γ2。这表明含有GluA 2 A643 V的AMPAR表现出新的功能增益，大大减缓了失活，显著降低了脱敏作用，并增加了谷氨酸敏感性。Perampanel是一种抗癫痫的AMPAR负变构调节剂，能够完全阻断GluA 2 A643 V/γ2电流，表明具有潜在的治疗疗效。随后将perampanel引入患者的治疗方案与癫痫发作负担显著降低、发育不良消退和明显发育获益相关。我们的研究表明，GRIA 2紊乱可能由功能获得性变体引起，这两种情况均预测并提示了perampanel的治疗疗效。Perampanel可能对其他功能获得型GRIA变体患者有益。
α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid‐type glutamate receptors (AMPARs) are ligand‐gated cationic channels formed from combinations of GluA1‐4 subunits. Pathogenic variants of GRIA1–4 have been described in patients with developmental delay, intellectual disability, autism spectrum disorder, and seizures, with GRIA2 variants typically causing AMPAR loss of function. Here, we identify a novel, heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V, NM_001083619.1) in a 1‐year‐old boy with epilepsy, developmental delay, and failure to thrive. We made patch‐clamp recordings to compare the functional and pharmacological properties of variant and wild‐type receptors expressed in HEK293 cells, with and without the transmembrane AMPAR regulatory protein γ2. This showed GluA2 A643V‐containing AMPARs to exhibit a novel gain of function, with greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity. Perampanel, an antiseizure AMPAR negative allosteric modulator, was able to fully block GluA2 A643V/γ2 currents, suggesting potential therapeutic efficacy. The subsequent introduction of perampanel to the patient's treatment regimen was associated with a marked reduction in seizure burden, a resolution of failure to thrive, and clear developmental gains. Our study reveals that GRIA2 disorder can be caused by a gain‐of‐function variant, and both predicts and suggests the therapeutic efficacy of perampanel. Perampanel may prove beneficial for patients with other gain‐of‐function GRIA variants.
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影响因子：
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影响因子：
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作者：
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通讯作者：
Tucci, Arianna