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Location of 29 mutations in the KCNQ2 gene and three mutations in the KCNQ3 gene from all studies. The predicted structure for KCNQ2 and KCNQ3 is six transmembrane domains interrupted by a pore region and intracellular N- and C-termini. Mutations are missense, splice site, insertions, deletions and nonsense for KCNQ2 , and missense only for KCNQ3 . 1 Moulard et al ., 2001; 2 Dedek et al ., 2001; 

Location of 29 mutations in the KCNQ2 gene and three mutations in the KCNQ3 gene from all studies. The predicted structure for KCNQ2 and KCNQ3 is six transmembrane domains interrupted by a pore region and intracellular N- and C-termini. Mutations are missense, splice site, insertions, deletions and nonsense for KCNQ2 , and missense only for KCNQ3 . 1 Moulard et al ., 2001; 2 Dedek et al ., 2001; 

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Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant generalized epilepsy of the newborn infant. Seizures occur repeatedly in the first days of life and remit by approximately 4 months of age. Previously our laboratory cloned two novel potassium channel genes, KCNQ2 and KCNQ3, and showed that they are mutated in patients with BF...

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... K1705 and accurately represents the natural course of the BFNC disorder. In this family, the seizures in 31 affected individuals (68%) ceased before the sixth week of life. In the literature and in the cases cited here, 29 mutations have been identi®ed in KCNQ2. All three mutations identi®ed in KCNQ3 are present in the pore region of the molecule (Fig. ...

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... The M-current activates at subthreshold potentials to regulate action potential firing of neurons (25,26). Reflecting its key role in controlling neuronal excitability, congenital mutations in KCNQ2 and KCNQ3 that alter M-current function are commonly associated with forms of early-onset epilepsy (27), including benign familial neonatal convulsions (BFNC) (28)(29)(30)(31) and the more severe early infantile epileptic encephalopathy (EIEE) (32)(33)(34). Activation of M-current hyperpolarizes neurons and suppresses membrane excitability, making the neuronal KCNQ channels prime therapeutic targets against epilepsy. ...
... Inherited mutations in KCNQ2 and KCNQ3 are frequently associated with neonatal epilepsies (27)(28)(29)(30)(31)(32)(33)(34). To explore whether the AO state E-M coupling in KCNQ2 and KCNQ3 has direct implications for human pathophysiology, we searched the National Center for Biotechnology Information (NCBI) ClinVar database for conserved AO state E-M coupling residues in KCNQ2 and KCNQ3 ( Fig. 2A and fig. ...
... This result may have some implications for why we observe far more disease-associated mutations in KCNQ2 compared to KCNQ3 and for the severity of disease manifestations. For instance, most BFNC mutations are found in KCNQ2 with less mutations identified in KCNQ3, whereas the EIEE mutations that cause a more severe form of childhood epilepsy are far more predominant in KCNQ2 (31,75). It should be noted that differential expression of KCNQ2 and KCNQ3 during development (expression of KCNQ2 preceding that of KCNQ3) (76) may also underlie the higher pathogenic impact of KCNQ2 versus KCNQ3 variants. ...
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... In vitro voltage-clamp studies of heterologously expressed recombinant human K V 7.2 channels have been informative regarding the functional consequences of disease-associated variants (14,(21)(22)(23)(24)(25)(26)(27)(28). Although valuable, these studies have been confounded by varied experimental strategies and expression systems employed by multiple independent laboratories. ...
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... Failure to follow this strategy will ultimately result in variants relevant only to the studied cohort and not necessarily applicable to other sub-populations diagnosed with the same inherited disorder. For example, BFNC/BFNS in human newborns was originally thought to be predisposed exclusively by mutations in the potassium channel encoding KCNQ2 gene on chromosome 20 [84][85][86][87]. Subsequently mutations in the KCNQ3 gene on chromosome 9 [87,88] and an inversion on chromosome 5 [89], were identified as additional loci. ...
... For example, BFNC/BFNS in human newborns was originally thought to be predisposed exclusively by mutations in the potassium channel encoding KCNQ2 gene on chromosome 20 [84][85][86][87]. Subsequently mutations in the KCNQ3 gene on chromosome 9 [87,88] and an inversion on chromosome 5 [89], were identified as additional loci. Consequently, the syndrome was sub-classified according to the associated genes, i.e. ...
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... Thus, the M-current plays a critical role in dynamically regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input (Brown and Adams, 1980;Constanti and Brown, 1981;Wang and McKinnon, 1995). Mutations in KCNQ2 and KCNQ3 associate with hyperexcitability phenotypes, including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE) (Singh et al., 1998(Singh et al., , 2003Soldovieri et al., 2014;Nappi et al., 2020). BFNE is a dominantly inherited condition affecting newborns and characterized by the occurrence of focal, multifocal or generalized seizures. ...
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In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1
... Two families with BFNE that had the same KCNQ2 PV as our patients have been previously reported [4,5]. As the parents of our patients refused genetic testing, it is uncertain whether this PV is familial or de novo. ...
... 2) Potassium channel KCNQ2 encodes the voltage-gated potassium channel subunit K v 7.2. KCNQ2 mutations were traditionally identified in benign familial neonatal epilepsy (BFNE) which were autosomal dominantly inherited [30,31]. BFNE presents seizures during the first week after birth which remit spontaneously with normal development [31,32]. ...
... KCNQ2 mutations were traditionally identified in benign familial neonatal epilepsy (BFNE) which were autosomal dominantly inherited [30,31]. BFNE presents seizures during the first week after birth which remit spontaneously with normal development [31,32]. Recently, de novo KCNQ2 mutations have been identified in patients with neonatal DEE [33][34][35][36][37][38][39][40]. ...
... However, these seizures are intractable, usually tonic, with burst suppression EEG pattern and accompany severe developmental delay [33][34][35][36]40]. Functional studies demonstrate that KCNQ2 mutations seen in BFNE are haploinsufficient, whereas mutations in KCNQ2 encephalopathy are dominant negative and result in a more severe reduction of channel current [31,41]. However, in rare cases, some KCNQ2 mutations in encephalopathy show an increase of channel current [42]. ...
... Kcnq3 encodes a subunit of the voltage-gated potassium channel whose mutations are associated with benign familial neonatal seizures (26). Vlgr1 encodes a receptor of the G protein-coupled adhesion receptor family, also named Mass1 (Monogenic, Audiogenic Seizure Susceptibility), this gene is associated with audiogenic epilepsy in the model Frings mice and related to the development of stereocilia in hair cells of the inner ear (27,28). ...
... In addition to the Frings mice, there are three other models that show mutation in the Vlgr1 gene. BUB/BnJ mice that have a mutation identical to the Frings model (Vlgr1/V2250X) (26), the knockin mice model (Vlgr1/del7TM) that does not express the transmembrane and cytoplasmic domains of VLGR1 (34), and the knockout mice model (Vlgr1-/-) that were developed by deletion directed from exon 2 to 4 of the Vlgr1 gene (36). All these models, like the Frings, are susceptible to audiogenic seizures, but the underlying mechanisms that relate VLGR1 to the occurrence of these seizures are still unknown (26,34,35). ...
... BUB/BnJ mice that have a mutation identical to the Frings model (Vlgr1/V2250X) (26), the knockin mice model (Vlgr1/del7TM) that does not express the transmembrane and cytoplasmic domains of VLGR1 (34), and the knockout mice model (Vlgr1-/-) that were developed by deletion directed from exon 2 to 4 of the Vlgr1 gene (36). All these models, like the Frings, are susceptible to audiogenic seizures, but the underlying mechanisms that relate VLGR1 to the occurrence of these seizures are still unknown (26,34,35). One of the hypotheses is based on the involvement of VLGR1 in CNS myelination. ...
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Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR model, of which 15,915 variants are SNPs and 1,170 INDELs. We filter the predicted variants by pre-established criteria and selected five for validation by Sanger sequencing. The genetic variant c.14198T>C in the Vlgr1 gene was confirmed in the WAR model. Vlgr1 encodes an adhesion receptor that is involved in the myelination process, in the development of stereocilia of the inner ear, and was already associated with the audiogenic seizures presented by the mice Frings. The transcriptional quantification of Vlgr1 revealed the downregulation this gene in the corpus quadrigeminum of WAR, and the protein modeling predicted that the mutated residue alters the structure of a domain of the VLGR1 receptor. We believe that Vlgr1 gene may be related to the predisposition of WAR to seizures and suggest the mutation Vlgr1 /Q4695R as putative causal variant, and the first molecular marker of the WAR strain.
... The variants arose de novo except one. Case 2 carried a paternal variant R333Q that had been reported to be associated with benign familial neonatal seizures (BFNS) (Singh et al., 2003). ...
... He achieved ESES remission at 7.1 years old and seizure-free at 8.1 years old with a remarkably developmental improvement, further supporting a diagnosis of ABPE. The R333Q variant had been previously reported in a family with BFNS (Singh et al., 2003). In our cohort, except for this case, the other seven affected families, including his father, were diagnosed with BFNS, whose seizure became free before the first year of life. ...
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Background Recently, the electroencephalogram pattern of electrical status epilepticus during sleep (ESES) had been reported in some genetic disorders, and most of them were noted with developmental and epileptic encephalopathy (DEE) or epileptic encephalopathy (EE). This study aimed to determine the genetic etiologies and clinical characteristics of ESES in DEE/EE. Methods We performed a cohort study in cases of DEE or EE with ESES. Tio-based genetic testing was performed in 74 cases and was analyzed to identify underlying variants. Results Pathogenic or likely pathogenic variants were identified in 17/74 cases, including KCNQ2 ( n = 6), KCNA2 ( n = 5), GRIN2A ( n = 3), SLC9A6 ( n = 1), HIVEP2 ( n = 1), and RARS2 ( n = 1). Eleven were boys. The median age at seizure onset was 6 months. ESES occurred at the mean age of 2.0 ± 1.2 years, predominant in the Rolandic region in 14 years. Twelve of 17 cases had the first stage of different epilepsy preceding ESES: 2/12 were diagnosed as Ohtahara syndrome, 2/12 were diagnosed as infantile spasms, 3/12 were diagnosed as DEE, and 5/12 were diagnosed as EE without the epileptic syndrome. Conclusion Monogenic variants explained over 20% of DEE/EE with ESES. ESES could be an age-related feature in genetic disorders and occurred after the first stage of different epilepsy. Both age-related factors and genetic etiology were suggested to play a role in the occurrence of ESES in genetic DEE/EE.
... Kcnq2 encodes the potassium channel subunit Kv7.2 that forms heterotetramers in axon membranes and generates non-inactivating hyperpolarizing M-type K + current to set the resting membrane potential 36,37 . Mutations in human KCNQ2 are associated with a phenotypic spectrum of neonatal-onset epilepsies extending from benign neonatal to severe developmental encephalopathy 38(p2), [39][40][41] . We combined in vivo/vitro electrophysiology and Kcnq2 pharmacology to examine SD characteristics of Kcnq2-cKO mice and compare them with a second axonal potassium channel seizure model, Kv1.1 deficient mice. ...
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Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link depolarizing molecular defects in Ca2+ flux, Na+ current in interneurons, and glial Na+-K+ ATPase with SD susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining SD threshold. In contrast, although gene mutations in voltage-gated potassium ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility, it is not known whether epileptogenic mutations that regulate membrane repolarization also modify SD threshold and propagation. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is an SD modulatory gene with significant control over the seizure-SD transition threshold, bihemispheric cortical expression, and diurnal temporal susceptibility. Chronic DC-band cortical EEG recording from behaving conditional Kcnq2 deletion mice (Emx1cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and SD. In contrast to the related potassium channel deficient model, Kv1.1-KO mice, spontaneous cortical SDs in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the nonselective Kv7.2 inhibitor XE991 to Kv1.1-KO mice reproduced the Kcnq2 cKO-like SD phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents directly and actively modulate SD properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical SD threshold, whereas pharmacological Kv7.2 activators elevate the threshold to multiple depolarizing and hypometabolic SD triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive SD regulatory gene, and point to SD as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as a potential adjunctive therapeutic target to inhibit SD incidence.
... Moreover, there are potassium voltage-gated channel subfamily Q member 2 and member 3(KCNQ2&KCNQ3) genes highly expressed in the brain, mostly in the hippocampus, temporal cortex, cerebellar cortex, and medulla oblongata. The mutations in KCNQ2 and KCNQ3 genes were identified to be associated with Benign familial neonatal seizures (BFNS) [9,10]. Table 2. Kv channels and their related genes. ...
Article
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Human hereditary epilepsy has been found related to ion channel mutations in voltage-gated channels (Na+, K+, Ca2+, Cl-), ligand gated channels (GABA receptors), and G-protein coupled receptors, such as Mass1. In addition, some transmembrane proteins or receptor genes, including PRRT2 and nAChR, and glucose transporter genes, such as GLUT1 and SLC2A1, are also about the onset of epilepsy. The discovery of these genetic defects has contributed greatly to our understanding of the pathology of epilepsy. This review focuses on introducing and summarizing epilepsy-associated genes and related findings in recent decades, pointing out related mutant genes that need to be further studied in the future.