Ma Mei-Gang, Liu Xiao-Rong, Wu Yuan, Wang Jie, Li Bing-Mei, Shi Yi-Wu, Su Tao, Li Bin, Liu De-Tian, Yi Yong-Hong, Liao Wei-Ping
Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Front Neurosci. 2021 Apr 7;15:629610. doi: 10.3389/fnins.2021.629610. eCollection 2021.
encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the mutations in the etiology of arrhythmogenic right ventricular dysplasia 2 and catecholaminergic polymorphic ventricular tachycardia. However, the relationship between gene and epilepsy is not determined. In this study, we screened for novel genetic variants in a group of 292 cases (families) with benign epilepsy of childhood with centrotemporal spikes (BECTS) by trio-based whole-exome sequencing. mutations were identified in five cases with BECTS, including one heterozygous frameshift mutation (c.14361dup/p.Arg4790Pro fs6), two heterozygous missense mutations (c.2353G > A/p.Asp785Asn and c.8574G > A/p.Met2858Ile), and two pairs of compound heterozygous mutations (c.4652A > G/p.Asn1551Ser and c.11693T > C/p.Ile3898Thr, c.7469T > C/p.Val2490Ala and c.12770G > A/p.Arg4257Gln, respectively). Asp785Asn was a missense mutation. All the missense mutations were suggested to be damaging by at least three web-based prediction tools. These mutations do not present or at low minor allele frequency in gnomAD database and present statistically higher frequency in the cohort of BECTS than in the control populations of gnomAD. Asp785Asn, Asn1551Ser, and Ile3898Thr were predicted to affect hydrogen bonds with surrounding amino acids. Three affected individuals had arrhythmia (sinus arrhythmia and occasional atrial premature). The two probands with compound heterozygous missense mutations presented mild cardiac structural abnormalities. Strong evidence from ClinGen Clinical Validity Framework suggested an association between variants and epilepsy. This study suggests that gene is potentially a candidate pathogenic gene of BECTS. More attention should be paid to epilepsy patients with mutations, which were associated with arrhythmia and sudden unexpected death in previous reports.
编码主要位于内质网膜上并调节细胞内钙浓度的兰尼碱受体2蛋白（RYR - 2）。RYR - 2蛋白广泛分布，在心脏和大脑中高表达。先前的研究已确定其突变与致心律失常性右室发育不良2型和儿茶酚胺能多形性室性心动过速的病因有关。然而，该基因与癫痫之间的关系尚未确定。在本研究中，我们通过基于三联体的全外显子测序，在一组292例（家系）伴有中央颞区棘波的儿童良性癫痫（BECTS）中筛选新的基因变异。在5例BECTS患者中鉴定出突变，包括1个杂合移码突变（c.14361dup/p.Arg4790Pro fs6）、2个杂合错义突变（c.2353G＞A/p.Asp785Asn和c.8574G＞A/p.Met2858Ile）以及2对复合杂合突变（分别为c.4652A＞G/p.Asn1551Ser和c.11693T＞C/p.Ile3898Thr，c.7469T＞C/p.Val2490Ala和c.12770G＞A/p.Arg4257Gln）。Asp785Asn是一个错义突变。所有错义突变至少被三种基于网络的预测工具提示具有损害性。这些突变在gnomAD数据库中不存在或次要等位基因频率较低，且在BECTS队列中的频率在统计学上高于gnomAD的对照人群。Asp785Asn、Asn1551Ser和Ile3898Thr被预测会影响与周围氨基酸的氢键。3例受影响个体出现心律失常（窦性心律失常和偶发房性早搏）。2例具有复合杂合错义突变的先证者存在轻度心脏结构异常。ClinGen临床有效性框架的有力证据表明这些变异与癫痫之间存在关联。本研究提示该基因可能是BECTS的候选致病基因。对于有该基因突变的癫痫患者应给予更多关注，先前报告显示这些突变与心律失常和心源性猝死有关。
