SHROOM4 Variants Are Associated With X-Linked Epilepsy With Features of Generalized Seizures or Generalized Discharges.
SHROOM4 Variants Are Associated With X-Linked Epilepsy With Features of Generalized Seizures or Generalized Discharges.
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SHROOM4 变异体与具有全身性癫痫发作或全身性放电特征的 X 连锁癫痫有关
DOI：
10.3389/fnmol.2022.862480
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发表时间：
2022
影响因子：
4.8
通讯作者：
Yi, Yong-Hong
中科院分区：
文献类型：
--
作者：
Bian, Wen-Jun;Li, Zong-Jun;Wang, Jie;Luo, Sheng;Li, Bing-Mei;Gao, Liang-Di;He, Na;Yi, Yong-Hong
关键词：
SHROOM 4基因编码一种肌动蛋白结合蛋白，在细胞骨架构建、突触形成和维持γ-氨基丁酸受体介导的抑制中起重要作用。在患有Stocco dos桑托斯型X连锁综合征性智力发育障碍（SDSX; OMIM# 300434）的患者中报告了SHROOM 4突变。在这项研究中，我们研究了SHROOM 4与癫痫之间的关系。对320例特发性全身性癫痫或特发性部分性癫痫患者进行了基于Trios的全外显子组测序。蛋白质建模用于评估变异的破坏性影响。在6例无智力障碍的原发性癫痫患者中发现了6种SHROOM 4基因的半合子错义突变，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。所有患者均表现为全身性癫痫发作或全身性放电。这些半合子变体在对照组中没有等位基因频率或等位基因频率极低，在病例组中的频率高于对照组。预测所有变体改变与周围氨基酸的氢键或降低蛋白质稳定性。在SDSX患者中报告的SHROOM 4变体大多是破坏性或重复性变体;相反，SHROOM 4变体都是错义变体，表明潜在的基因型-表型相关性。与SDSX相关的两个错义变体位于SHROOM 4蛋白的中间，而与特发性癫痫相关的变体位于N-末端PDZ结构域和C-末端ASD 2结构域周围。SHROOM 4可能是无智力障碍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机制。
SHROOM4 gene encodes an actin-binding proteins, which plays an important role in cytoskeletal architecture, synaptogenesis, and maintaining gamma-aminobutyric acid receptors-mediated inhibition. SHROOM4 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 SHROOM4 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 SHROOM4 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 SHROOM4 variants reported in patients with SDSX were mostly destructive or duplicative variants; in contrast, the SHROOM4 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. SHROOM4 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.
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影响因子：
1.3
作者：
Armanet N;Metay C;Brisset S;Deschenes G;Pineau D;Petit FM;Di Rocco F;Goossens M;Tachdjian G;Labrune P;Tosca L
通讯作者：
Tosca L
影响因子：
1.9
作者：
Isrie, M.;Froyen, G.;Van Esch, H.
通讯作者：
Van Esch, H.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
5.6
作者：
Samarut, Eric;Swaminathan, Amrutha;Drapeau, Pierre
通讯作者：
Drapeau, Pierre
用于预测遗传变异的计算机工具的优化：通过分子亚区域分层对基因进行个体化
影响因子：
9.5
作者：
Tang, Bin;Li, Bin;Liao, Wei-Ping
通讯作者：
Liao, Wei-Ping