DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect
To explore the phenotype spectrum of DEPDC5 variants 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 effect...
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Frontiers Media S.A.
2020-08-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00821/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liu Liu Liu Liu Zi-Rong Chen Zi-Rong Chen Hai-Qing Xu De-Tian Liu Yong Mao Han-Kui Liu Xiao-Rong Liu Peng Zhou Si-Mei Lin Bin Li Na He Tao Su Qiong-Xiang Zhai Heng Meng Wei-Ping Liao Yong-Hong Yi |
spellingShingle |
Liu Liu Liu Liu Zi-Rong Chen Zi-Rong Chen Hai-Qing Xu De-Tian Liu Yong Mao Han-Kui Liu Xiao-Rong Liu Peng Zhou Si-Mei Lin Bin Li Na He Tao Su Qiong-Xiang Zhai Heng Meng Wei-Ping Liao Yong-Hong Yi DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect Frontiers in Neuroscience DEPDC5 focal epilepsy febrile seizures genotype–phenotype correlation molecular sub-regional effect |
author_facet |
Liu Liu Liu Liu Zi-Rong Chen Zi-Rong Chen Hai-Qing Xu De-Tian Liu Yong Mao Han-Kui Liu Xiao-Rong Liu Peng Zhou Si-Mei Lin Bin Li Na He Tao Su Qiong-Xiang Zhai Heng Meng Wei-Ping Liao Yong-Hong Yi |
author_sort |
Liu Liu |
title |
DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect |
title_short |
DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect |
title_full |
DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect |
title_fullStr |
DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect |
title_full_unstemmed |
DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect |
title_sort |
depdc5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2020-08-01 |
description |
To explore the phenotype spectrum of DEPDC5 variants 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-related DEPDC5 variants were reviewed. The genotype–phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygous DEPDC5 mutation (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-related DEPDC5 variants 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 of DEPDC5 variants. This study suggested that the phenotypes of DEPDC5 variants vary from mild FEFS + /FS to severe MCD. Heterozygous DEPDC5 mutations 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 of DEPDC5 variants, explain severe phenotypes. |
topic |
DEPDC5 focal epilepsy febrile seizures genotype–phenotype correlation molecular sub-regional effect |
url |
https://www.frontiersin.org/article/10.3389/fnins.2020.00821/full |
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doaj-1b5a226905c6458c8167853cff9b79622020-11-25T03:41:06ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-08-011410.3389/fnins.2020.00821548027DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional EffectLiu Liu0Liu Liu1Zi-Rong Chen2Zi-Rong Chen3Hai-Qing Xu4De-Tian Liu5Yong Mao6Han-Kui Liu7Xiao-Rong Liu8Peng Zhou9Si-Mei Lin10Bin Li11Na He12Tao Su13Qiong-Xiang Zhai14Heng Meng15Wei-Ping Liao16Yong-Hong Yi17Institute of Neuroscience, 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, ChinaDepartment of Neurology, Xiaoshan First People’s Hospital, Hangzhou, ChinaInstitute of Neuroscience, 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, ChinaDepartment of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Neurology, Xuzhou Central Hospital, Affiliated Hospital of Southeast University, Xuzhou, ChinaInstitute of Neuroscience, 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, ChinaBGI-Shenzhen, Shenzhen, ChinaBGI-Shenzhen, Shenzhen, ChinaInstitute of Neuroscience, 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, ChinaInstitute of Neuroscience, 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, ChinaInstitute of Neuroscience, 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, ChinaInstitute of Neuroscience, 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, ChinaInstitute of Neuroscience, 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, ChinaInstitute of Neuroscience, 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, ChinaDepartment of Pediatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Neurology of the First Affiliated Hospital of Jinan University and Clinical Neuroscience Institute of Jinan University, Guangzhou, ChinaInstitute of Neuroscience, 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, ChinaInstitute of Neuroscience, 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, ChinaTo explore the phenotype spectrum of DEPDC5 variants 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-related DEPDC5 variants were reviewed. The genotype–phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygous DEPDC5 mutation (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-related DEPDC5 variants 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 of DEPDC5 variants. This study suggested that the phenotypes of DEPDC5 variants vary from mild FEFS + /FS to severe MCD. Heterozygous DEPDC5 mutations 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 of DEPDC5 variants, explain severe phenotypes.https://www.frontiersin.org/article/10.3389/fnins.2020.00821/fullDEPDC5focal epilepsyfebrile seizuresgenotype–phenotype correlationmolecular sub-regional effect |