Bian Wen-Jun, Li Zong-Jun, Wang Jie, Luo Sheng, Li Bing-Mei, Gao Liang-Di, He Na, Yi Yong-Hong
Institute of Neuroscience and Department of Neurology, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Front Mol Neurosci. 2022 May 17;15:862480. doi: 10.3389/fnmol.2022.862480. eCollection 2022.
gene encodes an actin-binding proteins, which plays an important role in cytoskeletal architecture, synaptogenesis, and maintaining gamma-aminobutyric acid receptors-mediated inhibition. mutations were reported in patients with the Stocco dos Santos type of X-linked syndromic intellectual developmental disorder (SDSX; OMIM# 300434). In this study, we investigated the association between and epilepsy.
Trios-based whole-exome sequencing was performed in a cohort of 320 cases with idiopathic generalized epilepsy or idiopathic partial epilepsy. Protein modeling was used to assess the damaging effects of variations.
Six hemizygous missense variants, including c.13C > A/p. Pro5Thr, c.3236C > T/p.Glu1079Ala, c.3581C > T/p.Ser1194Leu, c.4288C > T/p.Arg1430Cys, c.4303G > A/p.Val1435Met, c.4331C > T/p.Pro1444Leu, were identified in six cases with idiopathic epilepsy without intellectual disability. All patients presented with features of generalized seizures or generalized discharges. These hemizygous variants had no or extremely low allele frequencies in controls and showed statistically higher frequency in the case cohort than controls. All variants were predicted to alter hydrogen bond with surrounding amino acids or decreased protein stability. The variants reported in patients with SDSX were mostly destructive or duplicative variants; in contrast, the variants were all missense variants, suggesting a potential genotype-phenotype correlation. The two missense variants associated with SDSX were located in the middle of SHROOM4 protein, whereas variants associated with idiopathic epilepsy were located around the N-terminal PDZ domain and the C-terminal ASD2 domain.
was potentially a candidate pathogenic gene of idiopathic epilepsy without intellectual disability. The genotype-phenotype correlation and sub-regional effect helps understanding the mechanism underlying phenotypic variation.
[基因名称]编码一种肌动蛋白结合蛋白，该蛋白在细胞骨架结构、突触形成以及维持γ-氨基丁酸受体介导的抑制作用中发挥重要作用。据报道，在患有斯托科·多斯桑托斯型X连锁综合征性智力发育障碍（SDSX；OMIM#300434）的患者中存在[基因名称]突变。在本研究中，我们调查了[基因名称]与癫痫之间的关联。
对320例特发性全身性癫痫或特发性部分性癫痫患者进行基于三联体的全外显子测序。使用蛋白质建模来评估变异的有害影响。
在6例无智力残疾的特发性癫痫患者中鉴定出6个半合子错义变异，包括c.13C>A/p.Pro5Thr、c.3236C>T/p.Glu1079Ala、c.3581C>T/p.Ser1194Leu、c.4288C>T/p.Arg1430Cys、c.4303G>A/p.Val1435Met、c.4331C>T/p.Pro1444Leu。所有患者均表现出全身性发作或全身性放电的特征。这些半合子变异在对照组中的等位基因频率无或极低，且在病例组中的频率在统计学上高于对照组。所有变异均被预测会改变与周围氨基酸的氢键或降低蛋白质稳定性。在SDSX患者中报道的[基因名称]变异大多是破坏性或重复变异；相比之下，本研究中的[基因名称]变异均为错义变异，提示可能存在基因型-表型相关性。与SDSX相关的两个错义变异位于SHROOM4蛋白中部，而与特发性癫痫相关的变异位于N端PDZ结构域和C端ASD2结构域周围。
[基因名称]可能是无智力残疾的特发性癫痫的候选致病基因。基因型-表型相关性和亚区域效应有助于理解表型变异的潜在机制。
