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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;
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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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Citations
... KCNQ3 mutations are associated with benign neonatal seizures-2 (OMIM# 121201). 25 In this study, F336I in KCNQ3 was detected in two unrelated patients with benign neonatal seizures. The seizures of the two patients began at the age of 2 days and disappeared by the age of one year (high phenotype speci city). ...
... Missense mutations are the most common type of pathogenic mutation. 25 F336I in KCNQ3 was thus evaluated to be possibly causative by CCE (Table 2). ...
Interpreting sequence variants is a scientific challenge as well as a realistic task in clinical practice. The pathogenicity of a variant depends on not only its damage but also the genetic dependent quantity (GDQ, quantitative genetic function required for normal life) that differs in each gene but was not considered in previous protocols. We developed a clinical concordance evaluation (CCE) framework to evaluate the pathogenicity/causality of variants by comparing the clinical and genetic features of a patient with the pathogenic features of candidate genes, including phenotype specificity, pathogenic genotype, genotype-phenotype (severity) correlation, and inheritance, which are associated with GDQ. In 337 patients with epilepsy on genetic testing, 70 variants were evaluated as pathogenic/likely pathogenic by the American College of Medical Genetics and Genomics guidelines (ACMG). The CCE identified all these pathogenic/likely pathogenic variants but excluded the pathogenicity of one variant. The CCE identified an additional 13 possibly-causative, one likely-causative, and two causative variants, including a causative homozygous variant of MFSD8 associated with ceroid lipofuscinosis, which was evaluated as “uncertain significance” by ACMG. CCE is a framework with individualized criteria for the clinical/genetic abnormalities of patients and the pathogenic features of individual genes, potentially a practical protocol for individualized medicine.
... KCNQ3 mutations are associated with benign neonatal seizures-2 (OMIM# 121201). 24 In this study, F336I in KCNQ3 was detected in two unrelated patients with benign neonatal seizures. The seizures of the two patients began at the age of 2 days and disappeared by age of one year (high phenotype speci city). ...
Interpreting the sequence variants is a scientific challenge, as well as realistic task in clinical practice. The pathogenicity of variants depends not only on the damage but also the genetic dependent quantity (GDQ, quantitative genetic function required for normal life) that differs in each gene, but was not considered in previous protocols. We developed a clinical concordance evaluation (CCE) framework to evaluate the pathogenicity/causality of variants by comparing the clinical-genetic feature of a patient with the pathogenic feature of candidate gene, including phenotype specificity, pathogenic genotype, genotype-phenotype (severity) correlation, and inheritance, which are associated with the GDQ. In 337 patients with epilepsy on genetic test, 70 variants were evaluated as pathogenic/likely pathogenic by American College of Medical Genetics and Genomics guideline (ACMG). The CCE identified all these pathogenic/likely pathogenic variants, but excluded the pathogenicity of one variant. The CCE identified additional 13 possible-causative, one likely-causative, and two causative variants, including a causative homozygous variant of MFSD8 associated with ceroid lipofuscinosis, which was evaluated to be uncertain significant by ACMG. The CCE is a framework with individualized criteria on the clinical phenotype of patient and the pathogenic features of individual gene, being potentially a practical protocol for individualized medicine of future.
... KCNQ2 loss-of-function gene variants are tightly associated with neonatal-onset epileptic encephalopathy, but KCNQ3 and KCNQ5 loss-of-function mutations, and gain-of-function mutations in each of the three, are also associated with epilepsy of varying degrees of severity and developmental delay [8][9][10] . ...
Voltage-gated potassium (Kv) channels in the KCNQ subfamily serve essential roles in the nervous system, heart, muscle and epithelia. Different heteromeric KCNQ complexes likely serve distinct functions in the brain but heteromer subtype-specific small molecules for research or therapy are lacking. Rosemary (Salvia rosmarinus) is an evergreen plant used medicinally for millennia for neurological and other disorders. Here, we report that rosemary extract is a highly efficacious opener of heteromeric KCNQ3/5 channels, with weak effects on KCNQ2/3. Using functional screening we find that carnosic acid, a phenolic diterpene from rosemary, is a potent, highly efficacious, PIP2 depletion-resistant KCNQ3 opener with lesser effects on KCNQ5 and none on KCNQ1 or KCNQ2. Carnosic acid is also highly selective for KCNQ3/5 over KCNQ2/3 heteromers. Medicinal chemistry, in silico docking, and mutagenesis reveal that carboxylate-guanidinium ionic bonding with an S4-5 linker arginine underlies the KCNQ3 opening proficiency of carnosic acid, the effects of which on KCNQ3/5 suggest unique therapeutic potential and a molecular basis for ancient neurotherapeutic use of rosemary.
... This evidence signifies that the potassium channel plays a critical role in epilepsy. Accordingly, both KCNQ2 and KCNQ3 mutations are well-reported to be the main culprit behind the development of benign familial neonatal convulsion (Singh et al. 2003). In Kv 1.1 null mice, recurrent spontaneous seizures occurred all over the adult period owing to the loss of Kv 1.1 from the axonal region (Smart et al. 1998). ...
... Motor neuron degeneration is triggered by oligodendrocytes cell death, white matter damage, and axonal hyperexcitation (Santoro et al. 1990;Mogyoros et al. 1998;Fischer et al. 2004;Sarro et al. 2011;Shibuya et al. 2011;Philips et al. 2013;Nonneman et al. 2014;Maglemose et al. 2017;Zhou et al. 2017;Traiffort et al. 2021) 3 (Biervert et al. 1998;Singh et al. 1998Singh et al. , 2003Heurteaux et al. 2004;Strauss et al. 2006;Papale et al. 2009;Escayg and Goldin 2010;Veeramah et al. 2012;Estacion et al. 2014) 4 ...
The action potential conduction along the axon is highly dependent on the healthy interactions between the axon and myelin-producing glial cells. Myelin, which facilitates action potential, is the protective insulation around the axon formed by Schwann cells and oligodendrocytes in the peripheral (PNS) and central nervous system (CNS), respectively. Myelin is a continuous structure with intermittent gaps called nodes of Ranvier, which are the sites enriched with ion channels, transmembrane, scaffolding, and cytoskeletal proteins. Decades-long extensive research has identified a comprehensive proteome with strictly regularized localization at the node of Ranvier. Concurrently, axon-glia interactions at the node of Ranvier have gathered significant attention as the pathophysiological targets for various neurodegenerative disorders. Numerous studies have shown the alterations in the axon-glia interactions culminating in neurological diseases. In this review, we have provided an update on the molecular composition of the node of Ranvier. Further, we have discussed in detail the consequences of disruption of axon-glia interactions during the pathogenesis of various CNS and PNS disorders.
Graphical Abstract
... Chrna4 encodes a subunit of the nicotinic acetylcholine receptor, and its mutations are associated with nocturnal frontal lobe epilepsy. Kcnq3 encodes a subunit of the voltage-gated potassium channel with mutations associated with benign familial neonatal seizures [256]. Mutations in the Vlgr1 gene are associated with human epilepsy and with AE in the Frings mice (see above) [181]. ...
Animal models of epilepsy are of great importance in epileptology. They are used to study the mechanisms of epileptogenesis, and search for new genes and regulatory pathways involved in the development of epilepsy as well as screening new antiepileptic drugs. Today, many methods of modeling epilepsy in animals are used, including electroconvulsive, pharmacological in intact animals, and genetic, with the predisposition for spontaneous or refractory epileptic seizures. Due to the simplicity of manipulation and universality, genetic models of audiogenic epilepsy in rodents stand out among this diversity. We tried to combine data on the genetics of audiogenic epilepsy in rodents, the relevance of various models of audiogenic epilepsy to certain epileptic syndromes in humans, and the advantages of using of rodent strains predisposed to audiogenic epilepsy in current epileptology.
... 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. ...
KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening. We identified some epilepsy-linked mutations in KCNQ2 and KCNQ3 that disrupt E-M coupling. The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished by a mutation disrupting E-M coupling, suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.
... 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. ...
Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recording to assess at an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
... 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. ...
Juvenile idiopathic epilepsy (JIE) is a self-limiting neurological disorder with a suspected genetic predisposition affecting young Arabian foals of the Egyptian lineage. The condition is characterized by tonic-clonic seizures with intermittent post-ictal blindness, in which most incidents are sporadic and unrecognized. This study aimed to identify genetic components shared across a local cohort of Arabian foals diagnosed with JIE via a combined whole genome and targeted resequencing approach: Initial whole genome comparisons between a small cohort of nine diagnosed foals (cases) and 27 controls from other horse breeds identified variants uniquely shared amongst the case cohort. Further validation via targeted resequencing of these variants, that pertain to non-intergenic regions, on additional eleven case individuals revealed a single 19bp deletion coupled with a triple-C insertion (Δ19InsCCC) within the TRIM39-RPP21 gene readthrough that was uniquely shared across all case individuals, and absent from three additional Arabian controls. Furthermore, we have confirmed recent findings refuting potential linkage between JIE and other inherited diseases in the Arabian lineage, and refuted the potential linkage between JIE and genes predisposing a similar disorder in human newborns. This is the first study to report a genetic variant to be shared in a sub-population cohort of Arabian foals diagnosed with JIE. Further evaluation of the sensitivity and specificity of the Δ19InsCCC allele within additional cohorts of the Arabian horse is warranted in order to validate its credibility as a marker for JIE, and to ascertain whether it has been introduced into other horse breeds by Arabian ancestry.
... 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. ...
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. ...
