Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.
Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.
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DOI：
10.1093/braincomms/fcaa162
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发表时间：
2020
影响因子：
4.8
通讯作者：
Chebib M
中科院分区：
文献类型：
--
作者：
Absalom NL;Liao VWY;Kothur K;Indurthi DC;Bennetts B;Troedson C;Mohammad SS;Gupta S;McGregor IS;Bowen MT;Lederer D;Mary S;De Waele L;Jansen K;Gill D;Kurian MA;McTague A;Møller RS;Ahring PK;Dale RC;Chebib M
编码γ-氨基丁酸A型受体β3亚基的GABRB3基因变异与多种发育性和癫痫性脑病有关。通常，这些变异会导致功能丧失的分子表型，从而γ-氨基丁酸降低了导致癫痫发作的抑制效果。增强抑制性gaba能活性的药物，如硝西泮、苯巴比妥或维加巴林，有望弥补这一点，从而减少癫痫发作频率。然而，vigabatrin是一种抑制γ-氨基丁酸转氨酶以增加强直γ-氨基丁酸电流的药物，在治疗GABRB3变异体患者的癫痫发作方面取得了不同程度的成功：一些患者癫痫发作停止，但在一些患者中出现过敏反应，并伴有低张力、镇静和呼吸抑制。对vigabatrin反应良好的GABRB3变体涉及截断变体（p.a g194*），导致明显的功能丧失。我们假设对维加巴特林过敏的患者可能表现出不同的γ-氨基丁酸a受体表型。为了验证这一假设，我们评估了GABRB3 （p.Glu77Lys和p.Thr287Ile）的新生变异表型，这些变异与临床对维加巴林过敏的患者相关。我们将GABRB3 p.Glu77Lys和p.Thr287Ile变体引入到连接的突触和突触外γ-氨基丁酸a受体构建中，以类似于患者杂合GABRB3变体的γ-氨基丁酸a受体表达。将这些构建体的mRNA注射到爪蟾卵母细胞中，并通过双电极电压钳电生理测量每种受体的激活特性。结果显示，GABRB3 p.Glu77Lys和p.Thr287Ile变异具有非典型的功能获得分子表型，其特征是γ-氨基丁酸A的效力增加，而不改变估计的最大开放通道概率、失活动力学或绝对电流。对受体激活特性的建模表明，当低浓度γ-氨基丁酸介导紧张电流时，这两种受体的变体都会引起氯通量的增加。因此，我们认为vigabatrin的超敏反应是GABRB3变异体加剧gaba能强压电流的结果，在处方vigabatrin时需要谨慎。相比之下，在功能丧失变体中增加强直电流的药物策略可能是一种安全有效的治疗方法。本研究表明，功能基因组学可以解释抗癫痫药物的有益和不良作用，并建议在GABRB3明显功能丧失的患者中应考虑使用维加巴特林。这项研究阐明了与同一基因相关的遗传性癫痫患者对维加巴特林的显著不同反应背后的机制。Vigabatrin补偿了β3 γ-氨基丁酸受体亚基的截断，但可能会加剧与低张力、镇静和呼吸抑制相关的过敏患者的功能获得变异体。
Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants. This study elucidated the mechanism behind the markedly different response to vigabatrin in patients with genetic epilepsies associated with the same gene. Vigabatrin compensated for the truncation of a β3 γ-aminobutyric acid receptor subunit, but likely exacerbates gain-of-function variants with patients experiencing hypersensitivity associated with hypotonia, sedation and respiratory suppression.
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影响因子：
9.9
作者：
Johannesen, Katrine;Marini, Carla;Maljevic, Snezana
通讯作者：
Maljevic, Snezana
DOI：
10.1073/pnas.89.15.6726
发表时间：
1992-08-01
影响因子：
11.1
作者：
FRITSCHY, JM;BENKE, D;MOHLER, H
通讯作者：
MOHLER, H
影响因子：
48
作者：
Lux, AL;Edwards, SW;Osborne, JP
通讯作者：
Osborne, JP
影响因子：
4.6
作者：
Hernandez, Ciria C.;Zhang, Yujia;Macdonald, Robert L.
通讯作者：
Macdonald, Robert L.
影响因子：
5.6
作者：
Kuenzle, C;Steinlin, M;Schmitt, B
通讯作者：
Schmitt, B