scholarly journals Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Xinxiao Li ◽  
Shengnan Guo ◽  
Siying Xu ◽  
Zhangping Chen ◽  
Lei Wang ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Conditional Knockout ◽  
Wild Type ◽  
Temperature Dependent ◽  
Gene Encoding ◽  
Gaba A ◽  
Spontaneous Seizures ◽  
Clonic Seizures ◽  
Response To Temperature ◽  
Febrile Seizures Plus

AbstractMutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

Genetic epilepsy with febrile seizures plus

Neurology ◽  
2017 ◽  
Vol 89 (12) ◽  
pp. 1210-1219 ◽  
Author(s):  
Yue-Hua Zhang ◽  
Rosemary Burgess ◽  
Jodie P. Malone ◽  
Georgie C. Glubb ◽  
Katherine L. Helbig ◽  
...  
Keyword(s):  
Genetic Data ◽  
Febrile Seizures ◽  
Original Description ◽  
Molecular Data ◽  
Genetic Determinants ◽  
Genetic Epilepsy ◽  
Phenotypic Spectrum ◽  
Clonic Seizures ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

Objective:Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum.Methods:We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years.Results:We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene.Conclusion:As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.

Identification of a Novel Nonsense Variant in the SCN1A Gene that Causes Febrile Seizure Disorder

2017 ◽  
Vol 16 (04) ◽  
pp. 236-238
Author(s):  
Nabila MarchoudI ◽  
Abdelfettah Rouissi ◽  
Jamal Fekkak ◽  
Farah Jouali
Keyword(s):  
Febrile Seizure ◽  
Febrile Seizures ◽  
Seizure Disorder ◽  
Gene Encoding ◽  
Seizure Disorders ◽  
Severe Myoclonic Epilepsy ◽  
Epilepsy Gene ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus ◽  
Scn1a Gene

AbstractThe SCN1A gene, encoding for the voltage-gated sodium channel Nav1.1, is the most clinically relevant epilepsy gene, with most mutations having been documented in a spectrum of epilepsy syndromes, ranging from the relatively benign generalized epilepsy with febrile seizures plus (GEFS+) to severe myoclonic epilepsy in infancy (SMEI), and other rare febrile seizure disorders. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. In this case, we describe a novel nonsense pathogenic variant (NM_001202435.1; c.327C > G) in SCN1A in a 10-month Moroccan infant with febrile seizure disorder.

scholarly journals Growth Temperature Regulation of Host-Specific Modifications of Rhizobial Lipo-Chitin Oligosaccharides: The Function of nodX Is Temperature Regulated

2000 ◽  
Vol 13 (8) ◽  
pp. 808-820 ◽  
Author(s):  
Maurien M. A. Olsthoorn ◽  
Ellen Stokvis ◽  
Johan Haverkamp ◽  
Herman P. Spaink ◽  
Jane E. Thomas-Oates
Keyword(s):  
Growth Temperature ◽  
High Performance ◽  
Rhizobium Leguminosarum ◽  
High Performance Liquid Chromatographic ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Temperature Dependent ◽  
Gene Encoding ◽  
Two Temperatures ◽  
Liquid Chromatographic

Lipo-chitin oligosaccharides (LCOs) are usually produced and isolated for structural analysis from bacteria cultured under laboratory rather than field conditions. We have studied the influence of bacterial growth temperature on the LCO structures produced by different Rhizobium leguminosarum strains, using thin-layer chromatographic, high-performance liquid chromatographic, and mass spectrometric analyses. Wild-type R. leguminosarum bv. viciae A1 was shown to produce larger relative amounts of nodX-mediated, acetylated LCOs at 12°C than at 28°C, indicating that the activity of nodX (a gene encoding an LCO O-acetyl transferase) is temperature dependent. Interestingly, symbiotic resistance genes sym1 and sym2 found in primitive pea cultivars are also temperature sensitive, only being active at low temperatures, at which they block nodulation by R. leguminosarum bv. viciae strains lacking nodX. We therefore propose that the gene-for-gene relationship between plant and bacterium has a temperature-sensitive mechanism as an adaptation to environmental conditions. An R. leguminosarum bv. trifolii strain was also shown to produce larger relative amounts of nodX-mediated, acetylated LCOs at 12°C than at 28°C. The major components synthesized by the two strains are produced at both temperatures but in different relative amounts, while some minor components are only produced at one of the two temperatures.

scholarly journals Model systems for studying cellular mechanisms of SCN1A-related epilepsy

2016 ◽  
Vol 115 (4) ◽  
pp. 1755-1766 ◽  
Author(s):  
Soleil S. Schutte ◽  
Ryan J. Schutte ◽  
Eden V. Barragan ◽  
Diane K. O'Dowd
Keyword(s):  
Induced Pluripotent Stem Cell ◽  
Febrile Seizures ◽  
Model Systems ◽  
Dravet Syndrome ◽  
Response To Treatment ◽  
Patient Specific ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Induced Pluripotent ◽  
Febrile Seizures Plus

Mutations in SCN1A, the gene encoding voltage-gated sodium channel NaV1.1, cause a spectrum of epilepsy disorders that range from genetic epilepsy with febrile seizures plus to catastrophic disorders such as Dravet syndrome. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. Distinct effects of individual SCN1A mutations on neuronal function are likely to contribute to variation in disease severity and response to treatment in patients. Several model systems have been used to explore seizure genesis in SCN1A epilepsies. In this article we review what has been learned about cellular mechanisms and potential new therapies from these model systems, with a particular emphasis on the novel model system of knockin Drosophila and a look toward the future with expanded use of patient-specific induced pluripotent stem cell-derived neurons.

scholarly journals The Genetics of Temporal Lobe Epilepsy and Implications for Treatment

2007 ◽  
Vol 7 (4) ◽  
pp. 100-101
Author(s):  
Bassel W. Abou-Khalil
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Febrile Seizures ◽  
Temporal Lobectomy ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Quantitative Mr Imaging ◽  
Quantitative Mr ◽  
Febrile Seizures Plus

Temporal Lobe Epilepsy and GEFS+ Phenotypes Associated with SCN1B Mutations. Scheffer IE, Harkin LA, Grinton BE, Dibbens LM, Turner SJ, Zielinski MA, Xu R, Jackson G, Adams J, Connellan M, Petrou S, Wellard RM, Briellmann RS, Wallace RH, Mulley JC, Berkovic SF. Brain 2007;130(Pt 1):100–109. SCN1B, the gene encoding the sodium channel β1 subunit, was the first gene identified for generalized epilepsy with febrile seizures plus (GEFS+). Only three families have been published with SCN1B mutations. Here, we present four new families with SCN1B mutations and characterize the associated phenotypes. Analysis of SCN1B was performed on 402 individuals with various epilepsy syndromes. Four probands with missense mutations were identified. Detailed electroclinical phenotyping was performed on all available affected family members including quantitative MR imaging in those with temporal lobe epilepsy (TLE). Two new families with the original C121W SCN1B mutation were identified; novel mutations R85C and R85H were each found in one family. The following phenotypes occurred in the six families with SCN1B missense mutations: 22 febrile seizures, 20 febrile seizures plus, five TLE, three other GEFS+ phenotypes, two unclassified and ten unaffected individuals. All individuals with confirmed TLE had the C121W mutation; two underwent temporal lobectomy (one with hippocampal sclerosis and one without) and both are seizure free. We confirm the role of SCN1B in GEFS+ and show that the GEFS+ spectrum may include TLE alone. TLE with an SCN1B mutation is not a contraindication to epilepsy surgery.

scholarly journals Novel mutation of SCN9A gene causing generalized epilepsy with febrile seizures plus in a Chinese family

2020 ◽  
Vol 41 (7) ◽  
pp. 1913-1917 ◽  
Author(s):  
Tian Zhang ◽  
Mingwu Chen ◽  
Angang Zhu ◽  
Xiaoguang Zhang ◽  
Tao Fang
Keyword(s):  
Sodium Channel ◽  
Febrile Seizures ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Gene Encoding ◽  
Voltage Gated Sodium Channel ◽  
Α Subunit ◽  
Voltage Gated ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

Abstract Generalized epilepsy with febrile seizures plus (GEFS+) is a complex familial epilepsy syndrome. It is mainly caused by mutations in SCN1A gene, encoding type 1 voltage-gated sodium channel α-subunit (NaV1.1), and GABRA1 gene, encoding the α1 subunit of the γ-aminobutyric acid type A (GABAA) receptor, while seldom related with SCN9A gene, encoding the voltage-gated sodium channel NaV1.7. In this study, we investigated a Chinese family with an autosomal dominant form of GEFS+. DNA sequencing of the whole coding region revealed a novel heterozygous nucleotide substitution (c.5873A>G) causing a missense mutation (p.Y1958C). This mutation was predicted to be deleterious by three different bioinformatics programs (The polyphen2, SIFT, and MutationTaster). Our finding reports a novel likely pathogenic SCN9A Y1958C heterozygous mutation in a Chinese family with GEFS+ and provides additional supports that SCN9A variants may be associated with human epilepsies.

Altered PKA modulation in the Nav1.1 epilepsy variant I1656M

2013 ◽  
Vol 110 (9) ◽  
pp. 2090-2098 ◽  
Author(s):  
Shuai Liu ◽  
Ping Zheng
Keyword(s):  
Protein Kinases ◽  
Neuronal Excitability ◽  
Sodium Current ◽  
Febrile Seizures ◽  
Patch Clamp Technique ◽  
Gene Encoding ◽  
Α Subunit ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Febrile Seizures Plus

Genetic epilepsy with febrile seizures plus (GEFS+) is an inherited epilepsy that can result from mutations in at least four ion channel subunits. The majority of the known GEFS+ mutations have been identified in SCN1A, the gene encoding Nav1.1 α-subunit. Protein kinases as critical modulators of sodium channels have been closely related to the genesis of epilepsy. However, little is known about how protein kinases affect the GEFS+ mutant sodium channel. To gain insight into the protein kinases effect on channel properties and neuronal excitability of SCN1A mutant channels, we investigated the human SCN1A GEFS+ mutation I1656M by using whole cell patch-clamp technique and an established computational neuron model. The results showed that the PKA inhibition of sodium current amplitude significantly decreased in the I1656M mutant channels, but the PKC inhibition did not. The responses of the voltage-dependent activation and fast inactivation to PKA activator disappeared in the I1656M mutant channels, but the response of the voltage dependence of the slow inactivation did not. Computational model analysis suggested that changes of the I1656M mutant channel gating behaviors in response to PKA activation altered neuronal excitability. These results indicate that altered responses of the mutant channels to PKA signaling may impair the delicate balances between chemical and electrical harmony and lead to abnormal neuronal excitability.

Effects of an Autoregulatory Senescence-inhibitor Gene Construct on Nicotiana alata Link and Otto.

HortScience ◽  
1998 ◽  
Vol 33 (3) ◽  
pp. 519d-519 ◽  
Author(s):  
Kenneth R. Schroeder ◽  
Dennis P. Stimart
Keyword(s):  
Agrobacterium Tumefaciens ◽  
Plant Height ◽  
Dry Weight ◽  
Nicotiana Alata ◽  
Wild Type ◽  
Gene Encoding ◽  
Delayed Senescence ◽  
Gene Construct ◽  
Shoot Dry Weight ◽  
Inhibitor System

Nicotiana alata Link and Otto. was transformed via Agrobacterium tumefaciens encoding a senescence-specific promoter SAG12 cloned from Arabidopsis thaliana fused to a Agrobacterium tumefaciens gene encoding isopentenyl transferase (IPT) that catalyzes cytokinin synthesis. This was considered an autoregulatory senescence-inhibitor system. In 1996, we reported delayed senescence of intact flowers by 2 to 6 d and delayed leaf senescence of transgenic vs. wild-type N. alata. Further evaluations in 1997 revealed several other interesting effects of the SAG12-IPT gene construct. Measurement of chlorophyll content of mature leaves showed higher levels of both chlorophyll a and b in transgenic material under normal fertilization and truncated fertilization regimes. At 4 to 5 months of age transgenic plants expressed differences in plant height, branching, and dry weight. Plant height was reduced by 3 to 13 cm; branch counts increased 2 to 3 fold; and shoot dry weight increased up to 11 g over wild-type N. alata. These observations indicate the system is not tightly autoregulated and may prove useful to the floriculture industry for producing compact and more floriferous plants.

scholarly journals Putative transmembrane transporter modulates higher-level aggression in Drosophila

2017 ◽  
Vol 114 (9) ◽  
pp. 2373-2378 ◽  
Author(s):  
Budhaditya Chowdhury ◽  
Yick-Bun Chan ◽  
Edward A. Kravitz
Keyword(s):  
Causal Effect ◽  
Nerve Terminals ◽  
Rna Seq ◽  
Wild Type ◽  
Temperature Dependent ◽  
Number Of Genes ◽  
Interesting Family ◽  
Solute Carrier ◽  
Transmembrane Transporter ◽  
Selection Of

By selection of winners of dyadic fights for 35 generations, we have generated a hyperaggressive Bully line of flies that almost always win fights against the parental wild-type Canton-S stock. Maintenance of the Bully phenotype is temperature dependent during development, with the phenotype lost when flies are reared at 19 °C. No similar effect is seen with the parent line. This difference allowed us to carry out RNA-seq experiments and identify a limited number of genes that are differentially expressed by twofold or greater in the Bullies; one of these was a putative transmembrane transporter, CG13646, which showed consistent and reproducible twofold down-regulation in Bullies. We examined the causal effect of this gene on the phenotype with a mutant line for CG13646, and with an RNAi approach. In all cases, reduction in expression of CG13646 by approximately half led to a hyperaggressive phenotype partially resembling that seen in the Bully flies. This gene is a member of a very interesting family of solute carrier proteins (SLCs), some of which have been suggested as being involved in glutamine/glutamate and GABA cycles of metabolism in excitatory and inhibitory nerve terminals in mammalian systems.

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