Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies.
Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies.
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DOI：
10.1038/s41467-022-29280-x
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发表时间：
2022-04-05
影响因子：
16.6
通讯作者：
Ahring PK
中科院分区：
文献类型：
--
作者：
Absalom NL;Liao VWY;Johannesen KMH;Gardella E;Jacobs J;Lesca G;Gokce-Samar Z;Arzimanoglou A;Zeidler S;Striano P;Meyer P;Benkel-Herrenbrueck I;Mero IL;Rummel J;Chebib M;Møller RS;Ahring PK
许多患有发育性和癫痫性脑病的患者存在GABAA受体编码基因的变体。推测这些变体引起受体功能丧失，导致神经元GABA能活性降低。然而，具有GABAA受体变体的患者具有不同的临床表型，并且尽管可获得增强GABA能活性的药物，但许多患者难以治疗。在这里，我们发现44个致病性GABRB 3错义变异体分离成功能获得和功能丧失组，并且各自的患者显示出不同的临床表型。功能获得队列（n = 27例患者）的癫痫发作年龄更小，重度智力残疾风险更高，发作时局灶性癫痫发作，张力减退，治疗后无癫痫发作的可能性更低。发作时的热性惊厥仅限于功能丧失队列（n = 47例患者）。总体而言，GABRB 3变异增加GABA能活性的患者具有更严重的发育性和癫痫性脑病。这一矛盾的发现挑战了我们目前对癫痫中GABA能系统的理解，以及如何治疗患者。γ-氨基丁酸（GABAA）受体的遗传变异与早发性癫痫相关。在这里，作者表明，功能丧失或功能获得定义了临床结果，功能获得变异出乎意料地更严重。
Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated. Genetic variants of γ-aminobutyric acid (GABAA) receptors are associated with early onset epilepsies. Here, the authors show that functional loss or gain-of-function defines clinical outcomes, with gain-of-function variants unexpectedly more severe.
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影响因子：
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通讯作者：
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通讯作者：
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作者：
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通讯作者：
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