scholarly journals Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy

2021 ◽  
Author(s):  
Bina Santoro ◽  
Andrea Merseburg ◽  
Jacquelin Kasemir ◽  
Eric W Buss ◽  
Felix Leroy ◽  
...  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Inhibitory Neuron ◽  
Epileptic Encephalopathy ◽  
Na Channel ◽  
De Novo Mutations ◽  
Axon Terminals ◽  
Channel Gene ◽  
Gated Channel ◽  
Invaluable Tool

De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo mutations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drugresistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Hcn1G380D/+ animals had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from HCN1 patients, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the need to tailor effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.

scholarly journals The study of sodium and potassium channel gene single-nucleotide variation significance in non-mechanical forms of epilepsy

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ozada Khamdiyeva ◽  
Zhanerke Tileules ◽  
Gulminyam Baratzhanova ◽  
Anastassiya Perfilyeva ◽  
Leyla Djansugurova
Keyword(s):  
Ion Channel ◽  
Potassium Channel ◽  
De Novo ◽  
Potassium Ion ◽  
Dravet Syndrome ◽  
De Novo Mutations ◽  
Single Nucleotide ◽  
Channel Gene ◽  
Sodium And Potassium ◽  
Potassium Channel Gene

Abstract Background Epilepsy is one of the most common and heterogeneous neurological diseases. The main clinical signs of the disease are repeated symptomatic or idiopathic epileptic seizures of both convulsive and non-convulsive nature that develop against a background of lost or preserved consciousness. The genetic component plays a large role in the etiology of idiopathic forms of epilepsy. The study of the molecular genetic basis of neurological disorders has led to a rapidly growing number of gene mutations known to be involved in hereditary ion channel dysfunction. The aim of this research was to evaluate the involvement of single-nucleotide variants that modify the function of genes (SCN1A, KCNT1, KCNTС1, and KCNQ2) encoding sodium and potassium ion channel polypeptides in the development of epilepsy. Results De novo mutations in the sodium channel gene SCN1A c.5347G>A (p. Ala1783Thr) were detected in two patients with Dravet syndrome, with a deletion in exon 26 found in one. Three de novo mutations in the potassium channel gene KCNT1 c.2800G>A (p. Ala934Thr), were observed in two patients with temporal lobe epilepsy (TLE) and one patient with residual encephalopathy. Moreover, a control cohort matched to the case cohort did not reveal any SNVs among conditionally healthy individuals, supporting the pathogenic significance of the studied SNVs. Conclusion Our results are supported by literature data showing that the sodium ion channel gene SCN1A c.5347G>A mutation may be involved in the pathogenesis of Dravet syndrome. We also note that the c.2800G>A mutation in the potassium channel gene KCNT1 can cause not only autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) but also other forms of epilepsy. To treat pathogenetic mutations that accelerate the function of sodium and potassium ion channels, we recommend ion channel blockade drug therapy.

scholarly journals Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jennifer C. Wong ◽  
Kameryn M. Butler ◽  
Lindsey Shapiro ◽  
Jacquelyn T. Thelin ◽  
Kari A. Mattison ◽  
...  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Seizure Susceptibility ◽  
Pore Region ◽  
Behavioral Abnormalities ◽  
Spontaneous Seizures ◽  
Genetic Landscape ◽  
Mouse Lines

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.

De Novo Mutations inSLC35A2Encoding a UDP-Galactose Transporter Cause Early-Onset Epileptic Encephalopathy

2013 ◽  
Vol 34 (12) ◽  
pp. 1708-1714 ◽  
Author(s):  
Hirofumi Kodera ◽  
Kazuyuki Nakamura ◽  
Hitoshi Osaka ◽  
Yoshihiro Maegaki ◽  
Kazuhiro Haginoya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Mutations

De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study

2006 ◽  
Vol 5 (6) ◽  
pp. 488-492 ◽  
Author(s):  
Samuel F Berkovic ◽  
Louise Harkin ◽  
Jacinta M McMahon ◽  
James T Pelekanos ◽  
Sameer M Zuberi ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Sodium Channel ◽  
De Novo ◽  
De Novo Mutations ◽  
Channel Gene ◽  
Sodium Channel Gene

Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature

2017 ◽  
Vol 48 (05) ◽  
pp. 371-377 ◽  
Author(s):  
Tobias Dietel ◽  
Christina Evers ◽  
Katrin Hinderhofer ◽  
Rudolf Korinthenberg ◽  
Daniel Ezzo ◽  
...  
Keyword(s):  
De Novo ◽  
Involuntary Movement ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Guanine Nucleotide ◽  
Review Of Literature ◽  
De Novo Mutations ◽  
Guanine Nucleotide Binding Protein ◽  
Guanine Nucleotide Binding ◽  
Severe Epilepsy

AbstractMutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

scholarly journals Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes

2017 ◽  
Vol 3 (6) ◽  
pp. e199 ◽  
Author(s):  
Mohammed Uddin ◽  
Marc Woodbury-Smith ◽  
Ada Chan ◽  
Ledia Brunga ◽  
Sylvia Lamoureux ◽  
...  
Keyword(s):  
Brain Tissue ◽  
De Novo ◽  
Focal Cortical Dysplasia ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Chromosomal Microarray ◽  
Published Data ◽  
De Novo Mutations ◽  
Coding Region

Objective:To expand the clinical phenotype associated with STXBP1 gene mutations and to understand the effect of STXBP1 mutations in the pathogenesis of focal cortical dysplasia (FCD).Methods:Patients with STXBP1 mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing.Results:Seven patients with heterozygous de novo mutations affecting the coding region of STXBP1 were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for STXBP1, providing evidence for a somatic mechanism. Cell-type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within STXBP1. By contrast, ASD was rarely associated with mutations in this gene in our large cohorts.Conclusions:STXBP1 mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an STXBP1 somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for STXBP1-related epilepsy.

Biallelic Mutations in SLC1A2; an Additional Mode of Inheritance for SLC1A2-Related Epilepsy

2017 ◽  
Vol 49 (01) ◽  
pp. 059-062 ◽  
Author(s):  
Mirjana Gusic ◽  
Roman Günthner ◽  
Bader Alhaddad ◽  
Reka Kovacs-Nagy ◽  
Christine Makowski ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Genetic Mechanism ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Functional Studies ◽  
Additional Mode ◽  
Biallelic Mutations ◽  
Mode Of Inheritance

AbstractRecently, heterozygous de novo mutations in SCL1A2 have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in SCL1A2 (c.1421 + 1G > C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in SLC1A2 can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant SLC1A2-related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism.

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