DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect.

Liu Liu,Yong Mao,Na He,Na He,Xiao-Rong Liu,Wei-Ping Liao,Wei-Ping Liao,Zi-Rong Chen,Zi-Rong Chen,Zi-Rong Chen,Zi-Rong Chen,Si-Mei Lin,Qiong-Xiang Zhai,Peng Zhou,Peng Zhou,Heng Meng,Yong-Hong Yi,Yong-Hong Yi,Han-Kui Liu,Tao Su,Tao Su,Si-Mei Lin,Hai-Qing Xu,De-Tian Liu,Bin Li,Bin Li

doi:10.3389/fnins.2020.00821

Abstract

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.

Highlights

DEPDC5 gene (OMIM∗614191) encodes disheveled Egl-10 and pleckstrin (DEP) domain containing protein 5, which forms part of the GTPase-activating protein activity toward RAG complex 1, a repressor of the mammalian target of rapamycin signaling pathway that is closely related to epilepsies (Bar-Peled et al, 2013; Baldassari et al, 2019)
Among the 305 patients with focal epilepsies, eight DEPDC5 mutations were identified in 12 unrelated families (Figure 1 and Table 1, sequencing graph, see Supplementary Figure S1)
Truncating mutation p.Arg239∗ has been reported in cases of focal cortical dysplasia (FCD) and focal epilepsy (Ishida et al, 2013; Baulac et al, 2015; Baldassari et al, 2019), whereas mutation p.Arg838∗ has been identified in cases of sleep-related hypermotor epilepsy, frontal lobe epilepsy (FLE), or focal epilepsy (Baldassari et al, 2019)

Summary

Introduction

DEPDC5 gene (OMIM∗614191) encodes disheveled Egl-10 and pleckstrin (DEP) domain containing protein 5, which forms part of the GTPase-activating protein activity toward RAG complex 1, a repressor of the mammalian target of rapamycin (mTOR) signaling pathway that is closely related to epilepsies (Bar-Peled et al, 2013; Baldassari et al, 2019). DEPDC5 mutations have been demonstrated to be the most common cause of familial focal epilepsies (Dibbens et al, 2013). The phenotypes of DEPDC5 mutations included familial epilepsies such as familial focal epilepsy with variable foci (Dibbens et al, 2013), autosomal dominant (AD) nocturnal frontal epilepsy (Ishida et al, 2013; Picard et al, 2014), and familial temporal lobe epilepsy (TLE) (Ishida et al, 2013; Striano et al, 2015) and non-familial focal epilepsies, such as childhood epilepsy with centrotemporal spikes (rolandic epilepsy) (Lal et al, 2014) and epilepsy with continuous spikes and waves during slow-wave sleep (Ricos et al, 2016). DEPDC5 mutations have been occasionally identified in cases of epileptic spasms (Carvill et al, 2015); asymptomatic carriers were common across the DEPDC5 mutation-related families (Tsai et al, 2017). The phenotypic spectrum of DEPDC5 mutations requires further verification, and it is unknown whether the phenotypic variation is correlated with the genotypes of DEPDC5 mutations

Methods

Results

Conclusion