scholarly journals GABAA receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Shimian Qu ◽  
Mackenzie Catron ◽  
Chengwen Zhou ◽  
Vaishali Janve ◽  
Wangzhen Shen ◽  
...  
Keyword(s):  
Antiepileptic Drugs ◽  
Cortical Neurons ◽  
De Novo ◽  
Single Gene ◽  
Single Point ◽  
Type A ◽  
De Novo Mutation ◽  
Single Point Mutation ◽  
Absence Seizures ◽  
Atypical Absence

Abstract The Lennox–Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified in a patient with Lennox–Gastaut syndrome. To determine whether the mutation causes Lennox–Gastaut syndrome in vivo in mice and to elucidate its mechanistic effects, we generated the heterozygous Gabrb3+/D120N knock-in mouse and found that it had frequent spontaneous atypical absence seizures, as well as less frequent tonic, myoclonic, atonic and generalized tonic–clonic seizures. Each of these seizure types had a unique and characteristic ictal EEG. In addition, knock-in mice displayed abnormal behaviours seen in patients with Lennox–Gastaut syndrome including impaired learning and memory, hyperactivity, impaired social interactions and increased anxiety. This Gabrb3 mutation did not alter GABA type-A receptor trafficking or expression in knock-in mice. However, cortical neurons in thalamocortical slices from knock-in mice had reduced miniature inhibitory post-synaptic current amplitude and prolonged spontaneous thalamocortical oscillations. Thus, the Gabrb3+/D120N knock-in mouse recapitulated human Lennox–Gastaut syndrome seizure types and behavioural abnormalities and was caused by impaired inhibitory GABAergic signalling in the thalamocortical loop. In addition, treatment with antiepileptic drugs and cannabinoids ameliorated atypical absence seizures in knock-in mice. This congenic knock-in mouse demonstrates that a single-point mutation in a single gene can cause development of multiple types of seizures and multiple behavioural abnormalities. The knock-in mouse will be useful for further investigation of the mechanisms of Lennox–Gastaut syndrome development and for the development of new antiepileptic drugs and treatments.

scholarly journals Seizure Exacerbation by Antiepileptic Drugs

2005 ◽  
Vol 5 (5) ◽  
pp. 192-193 ◽  
Author(s):  
Jacqueline A. French
Keyword(s):  
Antiepileptic Drugs ◽  
De Novo ◽  
Focal Epilepsy ◽  
Juvenile Myoclonic Epilepsy ◽  
Absence Epilepsy ◽  
Absence Seizures ◽  
Incorrect Diagnosis ◽  
Juvenile Absence Epilepsy ◽  
Generalized Epilepsy

Worsening of Seizures by Oxcarbazepine in Juvenile Idiopathic Generalized Epilepsies Gelisse P, Genton P, Kuate C, Pesenti A, Baldy-Moulinier M, Crespel A Epilepsia 2004;45:1282–1286 Purpose Several studies have shown that carbamazepine (CBZ) may aggravate idiopathic generalized epilepsy (IGE). Oxcarbazepine (OXC) is a new drug chemically related to CBZ. We report six cases of juvenile IGE with a clear aggravation by OXC. Methods We retrospectively studied all patients with IGE first referred to our epilepsy department between January 2001 and June 2003 and treated with OXC. Results During this period, six patients were identified. All had an aggravation of their epilepsy in both clinical and EEG activities. OXC had been used because of an incorrect diagnosis of focal epilepsy or generalized tonic–clonic seizures (GTCSs) of undetermined origin (no syndromic classification of the epilepsy). Before OXC, only one patient had experienced a worsening of seizures with an inadequate drug (carbamazepine; CBZ). Four had juvenile myoclonic epilepsy, one had juvenile absence epilepsy, and one had IGE that could not be classified into a precise syndrome. OXC (dosage range, 300–1,200 mg/day) was used in monotherapy in all of them except for one patient. Aggravation consisted of a clear aggravation of myoclonic jerks (five cases) or de novo myoclonic jerks (one case). Three patients had exacerbation of absence seizures. One patient had worsened dramatically and had absence status, and one had de novo absences after OXC treatment. The effects of OXC on GTCSs were less dramatic, with no worsening in frequency in three and a slight increase in three. Conclusions OXC can be added to the list of antiepileptic drugs that can exacerbate myoclonic and absence seizures in IGE.

scholarly journals Recurrent de novo single point mutation on the gene encoding Na+/K+ pump results in epilepsy

2021 ◽  
Author(s):  
Hong-Ming Li ◽  
Wen-Bao Hu ◽  
Chun-Gu Hong ◽  
Ran Duan ◽  
Meng-Lu Chen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Point Mutation ◽  
De Novo ◽  
Memory Function ◽  
Single Point ◽  
Idiopathic Epilepsy ◽  
Single Point Mutation ◽  
Gene Encoding ◽  
Binding Function ◽  
Potassium Binding

AbstractThe etiology of epilepsy remains undefined in two-thirds of patients. Here, we identified a de novo mutation of ATP1A2 (c.2426 T>G, p.Leu809Arg), which encodes the α2 subunit of Na+/K+-ATPase, from a family with idiopathic epilepsy. This mutation caused seizures in the study patients. We generated the point mutation mouse model Atp1a2L809R, which recapitulated the epilepsy observed in the study patients. In Atp1a2L809R/WT mice, convulsions were observed and cognitive and memory function was impaired. This mutation affected the potassium binding function of the protein, disabling its ion transport ability, thereby increasing the frequency of nerve impulses. Our work revealed that ATP1A2L809R mutations cause a predisposition to epilepsy. Moreover, we first provide a point mutation mouse model for epilepsy research and drug screening.

scholarly journals UMP inhibition and sequential firing in aspartate transcarbamoylase open ways to regulate plant growth

2020 ◽  
Author(s):  
Leo Bellin ◽  
Francisco del Caño-Ochoa ◽  
Adrián Velázquez-Campoy ◽  
Torsten Möhlmann ◽  
Santiago Ramón-Maiques
Keyword(s):  
Plant Growth ◽  
Active Sites ◽  
De Novo ◽  
Feedback Inhibition ◽  
Single Point ◽  
Aspartate Transcarbamoylase ◽  
Single Point Mutation ◽  
Carbamoyl Phosphate ◽  
Pyrimidine Nucleotides ◽  
Sequential Firing

ABSTRACTPyrimidine nucleotides are essential to plant development. We proved that Arabidopsis growth can be inhibited or enhanced by down- or upregulating aspartate transcarbamoylase (ATC), the first committed enzyme for de novo biosynthesis of pyrimidines in plants. To understand the unique mechanism of feedback inhibition of this enzyme by uridine 5-monophosphate (UMP), we determined the crystal structure of the Arabidopsis ATC trimer free and bound to UMP, demonstrating that the nucleotide binds and blocks the active site. The regulatory mechanism relies on a loop exclusively conserved in plants, and a single-point mutation (F161A) turns ATC insensitive to UMP. Moreover, the structures in complex with a transition-state analog or with carbamoyl phosphate proved a mechanism in plant ATCs for sequential firing of the active sites. The disclosure of the unique regulatory and catalytic properties suggests new strategies to modulate ATC activity and to control de novo pyrimidine synthesis and plant growth.

scholarly journals Selection of Cytochrome b Mutants Is Rare among Plasmodium falciparum Patients Failing Treatment with Atovaquone-Proguanil in Cambodia

2020 ◽  
Vol 65 (3) ◽  
Author(s):  
Jessica T. Lin ◽  
Andreea Waltmann ◽  
Kara A. Moser ◽  
Zackary Park ◽  
Yu Bin Na ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Plasmodium Falciparum ◽  
De Novo ◽  
Single Point ◽  
Low Frequency ◽  
Multidrug Resistant ◽  
Minor Role ◽  
Single Point Mutation ◽  
Content Type ◽  
A Minor

ABSTRACT Atovaquone-proguanil remains effective against multidrug-resistant Plasmodium falciparum in Southeast Asia, but resistance is mediated by a single point mutation in cytochrome b (cytb) that can arise during treatment. Among 14 atovaquone-proguanil treatment failures in a clinical trial in Cambodia, only one recrudescence harbored the cytb mutation Y268C. Deep sequencing did not detect the mutation at baseline or in the first 3 days of treatment, suggesting that it arose de novo. Further sequencing across cytb similarly found no low-frequency cytb mutations that were up-selected from baseline to recrudescence. Copy number amplification in dihydroorotate dehydrogenase (DHODH) and cytb as markers of atovaquone tolerance was also absent. Cytb mutation played a minor role in atovaquone-proguanil treatment failures in an active comparator clinical trial.

scholarly journals Genomic Mechanisms of Physiological and Morphological Adaptations of Limestone Langurs to Karst Habitats

2019 ◽  
Vol 37 (4) ◽  
pp. 952-968
Author(s):  
Zhijin Liu ◽  
Liye Zhang ◽  
Zhongze Yan ◽  
Zhijie Ren ◽  
Fengming Han ◽  
...  
Keyword(s):  
De Novo ◽  
Morphological Evolution ◽  
Single Point ◽  
Hair Follicles ◽  
Single Point Mutation ◽  
Plant Resources ◽  
De Novo Genome Assembly ◽  
High Calcium ◽  
Karst Habitats

Abstract Knowledge of the physiological and morphological evolution and adaptation of nonhuman primates is critical to understand hominin origins, physiological ecology, morphological evolution, and applications in biomedicine. Particularly, limestone langurs represent a direct example of adaptations to the challenges of exploiting a high calcium and harsh environment. Here, we report a de novo genome assembly (Tfra_2.0) of a male François’s langur (Trachypithecus francoisi) with contig N50 of 16.3 Mb and resequencing data of 23 individuals representing five limestone and four forest langur species. Comparative genomics reveals evidence for functional evolution in genes and gene families related to calcium signaling in the limestone langur genome, probably as an adaptation to naturally occurring high calcium levels present in water and plant resources in karst habitats. The genomic and functional analyses suggest that a single point mutation (Lys1905Arg) in the α1c subunit of the L-type voltage-gated calcium channel Cav1.2 (CACNA1C) attenuates the inward calcium current into the cells in vitro. Population genomic analyses and RNA-sequencing indicate that EDNRB is less expressed in white tail hair follicles of the white-headed langur (T. leucocephalus) compared with the black-colored François’s langur and hence might be responsible for species-specific differences in body coloration. Our findings contribute to a new understanding of gene–environment interactions and physiomorphological adaptative mechanisms in ecologically specialized primate taxa.

scholarly journals Mowat-Wilson syndrome: literature review and case series

2021 ◽  
Vol 16 (3) ◽  
pp. 10-20
Author(s):  
M. Yu. Bobylova ◽  
V. S. Kakaulina ◽  
M. O. Abramov ◽  
K. Yu. Mukhin
Keyword(s):  
De Novo ◽  
Heart Defects ◽  
Case Reports ◽  
Genetic Disorder ◽  
Epileptiform Activity ◽  
Age At Onset ◽  
Case Series ◽  
Facial Dysmorphism ◽  
Absence Seizures ◽  
Atypical Absence

Mowat-Wilson syndrome (MWS) is a rare genetic disorder characterized by a combination of the following signs: 1) facial dysmorphism (wide nose, broad medial eyebrows, pronounced chin, and open mouth); 2) mental retardation; 3) abnormalities of internal organs (congenital heart defects, Hirschsprung's disease, hypospadias/cryptorchidism). The disease is associated with a heterozygous pathogenic mutation in the ZEB2 gene. More than 80 % of MWS patients are diagnosed with epilepsy, the onset of which is usually observed in infancy. Patents have focal motor seizures, atypical absence seizures, generalized convulsive seizures. Epileptic seizures are often triggered by fever; some children are resistant to therapy. MWS patients have a specific phenotype (blue eyes, fair hair, wide-based gait, frequent laughter, limited or absent expressive language) that requires differential diagnosis with Angelman syndrome (caused by a mutation in the UBE3A gene). MWS was described in 1998, but there have been no case reports in the Russian literature yet. We report 4 cases of MWS in children aged 2 to 13 years treated in the Svt. Luka's Institute of Neurology and Epilepsy. In all of these patients, we identified a heterozygous de novo deletion in the ZEB2 gene. Epilepsy was observed in all patients. Mean age at onset was 13 months. All children had focal motor seizures and atypical absence seizures. None of them had tonic-clonic seizures or status epilepticus. The analysis of electroencephalograms showed that patients with a lower index of epileptiform activity tend to have better development and vice versa: children with a high index of epileptiform activity during sleep had more severe developmental delay.

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