Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy

Hirose, Shinichi

doi:10.1016/b978-0-444-63326-2.00003-x

Cited by 140 publications

(105 citation statements)

References 120 publications

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“…These data are consistent with a functional decline in GABAergic neurons, which may contribute to DS epileptogenesis [11]. These results are encouraging that patient-derived iPSC models can be utilized in human epilepsy research.…”

supporting

confidence: 76%

Dravet Syndrome

Rizk¹

2014

JNSK

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supporting

confidence: 76%

Dravet Syndrome

Rizk¹

2014

JNSK

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“…A single nucleotide polymorphism at the promoter region of GABRB3 (T>C substitution in position −897, numbering with respect to the initiator methionine of exon 1a), which leads to reduction of the promoter's transcriptional ability, has been associated with childhood absence epilepsy in previous studies 12. Other researchers have reported that a rare GABRB3 single nucleotide polymorphism (c.31C>T; p.Pro11Ser)15 and other variants (c.44C>T; p.Ser15Phe, and c.94G>A; p.Gly32Arg) (NM_021912.4) are linked with childhood absence epilepsy phenotypes associated with eyelid myoclonus and generalized tonic–clonic seizures 6, 11. Probands had typical generalized 3Hz spike and wave discharges during childhood, with clinical symptoms later remitting, without neurological sequelae.…”

Section: Discussionmentioning

confidence: 94%

“…The same mutations were not found in 630 healthy ethnically and sex‐matched comparison individuals in one study. However, p.Pro11Ser was later described in an asymptomatic individual, suggesting it may be a rare single nucleotide polymorphism 6, 15. Interestingly, genetic variants implicated in childhood absence epilepsy are clustered much closer to the N‐terminal domain of the protein than those identified in GABRB3 early infantile epileptic encephalopathy (Fig.…”

Section: Discussionmentioning

confidence: 97%

GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy

Papandreou

McTague²,

Trump

et al. 2015

Develop Med Child Neuro

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The gamma‐aminobutyric acid type A receptor β3 gene (GABRB3) encodes the β3‐subunit of the gamma‐aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signalling within the central nervous system. Recently, GABRB3 mutations have been identified in a few patients with infantile spasms and Lennox–Gastaut syndrome. We report the clinical and electrographic features of a novel case of GABRB3‐related early‐onset epileptic encephalopathy. Our patient presented with neonatal hypotonia and feeding difficulties, then developed pharmacoresistant epileptic encephalopathy, characterized by multiple seizure types from 3 months of age. Electroencephalography demonstrated ictal generalized and interictal multifocal epileptiform abnormalities. Using a SureSelectXT custom multiple gene panel covering 48 early infantile epileptic encephalopathy/developmental delay genes, a novel de novo GABRB3 heterozygous missense mutation, c.860C>T (p.Thr287Ile), was identified and confirmed on Sanger sequencing. GABRB3 is an emerging cause of early‐onset epilepsy. Novel genetic technologies, such as whole‐exome/genome sequencing and multiple gene panels, will undoubtedly identify further cases, allowing more detailed electroclinical delineation of the GABRB3‐related genotypic and phenotypic spectra.

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“…Human absence epilepsy is associated with mutations in the genes encoding the  5 ,  3 , or  2 subunits of the GABA A receptor (Hirose, 2014) and the amount of the  3 subunit in the NRT has been shown to be reduced in WAG/Rij rats as compared to non-epileptic control rats (Gauguier et al, 2004;Liu et al, 2007); instead, GABA A receptors are preserved in the neocortex of WAG/Rij epileptic rats, which are defective in several GABA B receptor isoforms (Liu et al, 2007;Merlo et al, 2007).…”

Section: Gabamentioning

confidence: 99%

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

128

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development.Neuroscience and Biobehavioral Reviews http://dx.doi.org/10. 1016/j.neubiorev.2016.09.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial "insult" responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then nongenetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.

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Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy

Cited by 140 publications

References 120 publications

Dravet Syndrome

Dravet Syndrome

GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

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