Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant
Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant
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DOI：
10.1007/s00439-021-02416-7
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发表时间：
2022-01-15
期刊：
影响因子：
5.3
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Hamanaka, Kohei;Miyoshi, Keita;Matsumoto, Naomichi
Xq25上的GRIA3编码谷氨酸嗜离子受体AMPA 3型（GluA3），这是介导神经传递的突触后谷氨酸门控离子通道的一个亚基。GRIA3中的半合子功能丧失（LOF）变异导致男性个体的神经发育障碍（NDD）。在这里，我们报告了一名男性患者的GRIA3基因功能获得（GOF）变异。我们利用全外显子组测序在一名患有NDD的男孩中发现了一种半合子从头错义变异：c.1844C > T （p.a ala615val）。他的神经症状，如高张力和反射亢进，与先前的LOF GRIA3变异病例相反。卡马西平抑制突触前谷氨酸释放，改善了癫痫发作和高张力。膜片钳记录显示，人类GluA3突变体（p.a ala615val）具有较慢的脱敏和失活动力学。表达人类GluA3突变体和Lurcher突变体（导致离子通道泄漏）的果蝇表现出发育缺陷，而表达其中任何一种突变体的果蝇则没有发育缺陷。总的来说，这些结果表明p.a ala615val具有GOF效应。GRIA3 GOF变异可能导致与LOF变异不同的NDD表型，抑制谷氨酸能神经传递的药物可能改善这种表型。本研究将有助于完善gria3相关ndd的临床管理。
GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.