Pediatric brain tumors are highly associated with epileptic seizures¹. However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy². To do so, we developed a mouse model harboring the BRAF^V600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAF^V600E mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAF^V600E-induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAF^V600E inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.

中文翻译：

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BRAF体细胞突变有助于小儿脑肿瘤的固有癫痫发生性。

小儿脑肿瘤与癫痫发作高度相关¹。但是，它们的致癫痫机制尚不清楚。在这里，我们显示，在发展中的神经元中，致癌性的BRAF体细胞突变p.Val600Glu（V600E）是神经节胶质瘤（顽固性癫痫的主要原因之一）²内在的癫痫发生性的基础。为此，我们开发了一种在早期大脑发育过程中携带BRAF ^V600E体细胞突变的小鼠模型，以反映最频繁的突变及其起源和时机。其中，BRAF ^V600E在大脑发育过程中祖细胞中发生的突变导致获得了神经元谱系细胞内在的癫痫发生特性，而致瘤特性则归因于神经胶质谱系细胞的高增殖。对具有突变的患者脑组织的RNA测序分析表明，BRAF ^V600E诱导的癫痫发生是由RE1沉默转录因子（REST）介导的，REST是与癫痫病相关的离子通道和神经递质受体的调节剂。此外，我们发现通过FDA批准的BRAF ^V600E可以大大减轻小鼠的癫痫发作抑制剂vemurafenib以及Rest的各种遗传抑制作用。因此，这项研究提供了BRAF体细胞突变有助于小儿脑肿瘤内在癫痫发生的直接证据，并表明BRAF和REST可能是顽固性癫痫的治疗靶点。