DEPDC5Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect
DEPDC5Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect
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DEPDC5变异与皮质发育畸形和局灶性癫痫伴热性惊厥加/热性惊厥相关：分子亚区域效应的作用
DOI：
10.3389/fnins.2020.00821
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发表时间：
2020-08-11
影响因子：
4.3
通讯作者：
Yi, Yong-Hong
中科院分区：
文献类型：
--
作者：
Liu, Liu;Chen, Zi-Rong;Yi, Yong-Hong
为了探索DEPDC 5变异体的表型谱和表型变异的可能机制，我们对305例局灶性癫痫患者和91例全身性癫痫患者进行了靶向下一代测序。进行蛋白质建模以预测错义突变的影响。所有先前报告的癫痫相关DEPDC 5变异体进行了审查。分析了基因型-表型相关性及其分子亚区域意义。我们在1例局灶性皮质发育不良患者中发现了一个纯合DEPDC 5突变（p.Pro1031His），在11个轻度局灶性癫痫家系中发现了8个杂合突变，其中包括8个局灶性癫痫伴热性惊厥+/热性惊厥（FEFS + /FS）家系中的13例患者。突变包括一个终止密码子突变（p.Ser1601_Ter1604del_ext133）、三个截短突变（p.Val151Serfs*27、p.Arg239* 和p.Arg838*）和四个错义突变（p.Tyr7Cys、p.Tyr836Cys、p.Pro1031His和p.Gly1545Ser），这些突变被预测会影响氢键和蛋白质稳定性。对癫痫相关DEPDC 5变异的分析显示，皮质发育畸形（MCD）的无效突变频率高于无MCD的患者。MCD相关的杂合错义突变聚集在结合排列结构轴（SABA）结构域，靠近NPRL 2/NPRL 3复合物的结合位点，而FEFS + /FS相关的杂合错义突变则远离结合位点。四个方面的证据和一个可能的亚区域暗示证据表明MCD和FEFS + /FS是DEPDC 5变异体的表型。本研究提示DEPDC 5变异体的表型从轻度FEFS + /FS到重度MCD不等。异源DEPDC 5突变通常致病性较低，通常与轻度表型相关。双等位基因突变和体细胞突变的二次打击，以及基因型-表型相关性和DEPDC 5变异的亚区域意义，解释了严重的表型。
To explore the phenotype spectrum ofDEPDC5variants and the possible mechanisms underlying phenotypical variation, we performed targeted next-generation sequencing in 305 patients with focal epilepsies and 91 patients with generalized epilepsies. Protein modeling was performed to predict the effects of missense mutations. All previously reported epilepsy-relatedDEPDC5variants were reviewed. The genotype-phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygousDEPDC5mutation (p.Pro1031His) in a case with focal cortical dysplasia and eight heterozygous mutations in 11 families with mild focal epilepsies, including 13 patients in eight families with focal epilepsy with febrile seizures plus/febrile seizures (FEFS + /FS). The mutations included one termination codon mutation (p.Ser1601_Ter1604del_ext133), three truncating mutations (p.Val151Serfs*27, p.Arg239*, and p.Arg838*), and four missense mutations (p.Tyr7Cys, p.Tyr836Cys, p.Pro1031His, and p.Gly1545Ser) that were predicted to affect hydrogen bonds and protein stability. Analysis on epilepsy-relatedDEPDC5variants revealed that malformations of cortical development (MCDs) had a tendency of higher frequency of null mutations than those without MCD. MCD-associated heterozygous missense mutations were clustered in structural axis for binding arrangement (SABA) domain and close to the binding sites to NPRL2/NPRL3 complex, whereas those associated with FEFS + /FS were a distance away from the binding sites. Evidence from four aspects and one possible evidence from sub-regional implication suggested MCD and FEFS + /FS as phenotypes ofDEPDC5variants. This study suggested that the phenotypes ofDEPDC5variants vary from mild FEFS + /FS to severe MCD. HeterozygousDEPDC5mutations are generally less pathogenic and commonly associated with mild phenotypes. Bi-allelic mutations and second hit of somatic mutations, together with the genotype-phenotype correlation and sub-regional implication ofDEPDC5variants, explain severe phenotypes.