The GABAA Receptor γ2 Subunit (R43Q) Mutation in Febrile Seizures

Hancılı, Suna; Önal, Zehra Esra; Ata, Pınar; Karatoprak, Elif Yüksel; Gürbüz, Tamay; Bostancı, Muharrem; Paçal, Yakup; Nuhoğlu, Çağatay; Ceran, Ömer

doi:10.1016/j.pediatrneurol.2014.01.002

Cited by 7 publications

(3 citation statements)

References 28 publications

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“…Genetic factors play a key role in the development and severity of genetic generalized epilepsy (GGE). Epilepsy-causing mutations have been identified in several GABA A receptor (GABA A R) subunits, including α1, β3, γ2, and δ subunits (Baulac et al, 2001 ; Wallace et al, 2001 ; Cossette et al, 2002 ; Harkin et al, 2002 ; Kananura et al, 2002 ; Dibbens et al, 2004 , 2009 ; Audenaert et al, 2006 ; Maljevic et al, 2006 ; Sun et al, 2008 ; Tanaka et al, 2008 ; Lachance-Touchette et al, 2010 , 2011 ; Shi et al, 2010 ; Klassen et al, 2011 ; Carvill et al, 2013 , 2014 ; Epi et al, 2013 ; Tian et al, 2013 ; Hancili et al, 2014 ; Ishii et al, 2014 ; Johnston et al, 2014 ). GABA A Rs are ligand-gated ion channels that are permeable to chloride and bicarbonate anions and mediate most of cortical inhibitory neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner

Lachance-Touchette

Choudhury

Stoica

et al. 2014

Front. Cell. Neurosci.

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Mutations in genes encoding for GABAA receptor subunits is a well-established cause of genetic generalized epilepsy. GABA neurotransmission is implicated in several developmental processes including neurite outgrowth and synapse formation. Alteration in excitatory/inhibitory synaptic activities plays a critical role in epilepsy, thus here we investigated whether mutations in α1 subunit of GABAA receptor may affect dendritic spine and GABAergic bouton formation. In particular, we examined the effects of three mutations of the GABRA1 gene (D219N, A322D and K353delins18X) that were found in a cohort of French Canadian families with genetic generalized epilepsy. We used a novel single-cell genetic approach, by preparing cortical organotypic cultures from GABRA1flox/flox mice and simultaneously inactivating endogenous GABRA1 and transfecting mutant α1 subunits in single glutamatergic pyramidal cells and basket GABAergic interneurons by biolistic transfection. We found that GABRA1−/− GABAergic cells showed reduced innervation field, which was rescued by co-expressing α1-A322D and α1-WT but not α1-D219N. We further found that the expression of the most severe GABRA1 missense mutation (α1-A322D) induced a striking increase of spine density in pyramidal cells along with an increase in the number of mushroom-like spines. In addition, α1-A322D expression in GABAergic cells slightly increased perisomatic bouton density, whereas other mutations did not alter bouton formation. All together, these results suggest that the effects of different GABAAR mutations on GABAergic bouton and dendritic spine formation are specific to the mutation and cannot be always explained by a simple loss-of-function gene model. The use of single cell genetic manipulation in organotypic cultures may provide a better understanding of the specific and distinct neural circuit alterations caused by different GABAA receptor subunit mutations and will help define the pathophysiology of genetic generalized epilepsy syndromes.

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Section: Introductionmentioning

confidence: 99%

Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner

Lachance-Touchette

Choudhury

Stoica

et al. 2014

Front. Cell. Neurosci.

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“…The complexity is reflected by multiple genes causing specific epilepsy syndromes that are clinically indistinguishable as well as genetic variants which may impact on the severity of the disease phenotypes [ 45 ]. Mutations of GABA A Rs have been identified as one of the primary genetic causes of epilepsy [ 20 , 22 , 25 , 25 , 28 , [32] , [33] , [34] , [35] , 38 , 42 , 45 , 48 , 80 , 80 , 81 ], but this phenomenon is not well understood, which is a challenge for the development of effective personalized treatment and management of epilepsy conditions. The advancements in neuroimaging and genetics have revealed that, while essential, the electro-clinical characterization of epilepsy syndromes alone is insufficient for personalized treatment strategies and a deeper comprehension of the fundamental mechanisms causing seizures [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach

Arslan

2023

Heliyon

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“…A missense mutation (R82Q) in the GABRG2 was found in an Australian family and results in an autosomal dominant inherited form of CAE and FS (Wallace et al, 2001;Hancili et al, 2014). Arginine 82, located in the high-affinity benzodiazepine-binding region, abolishes diazepam-potentiated currents in recombinant receptors expressed in X. laevis oocytes but does not affect Zn 21 sensitivity.…”

Section: A Large French Familymentioning

confidence: 99%

Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy

Chuang

Reddy

2017

J Pharmacol Exp Ther

115

114

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GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classic epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology. GABA-A receptors are the prime targets for neurosteroids (NSs). However, GABA-A receptors are not static but undergo rapid changes in their number or composition in response to the neuroendocrine milieu. This review describes the recent advances in the genetic and neuroendocrine control of extrasynaptic and synaptic GABA-A receptors in epilepsy and its impact on neurologic conditions. It highlights the current knowledge of GABA genetics in epilepsy, with an emphasis on the neuroendocrine regulation of extrasynaptic GABA-A receptors in network excitability and seizure susceptibility. Recent advances in molecular regulation of extrasynaptic GABA-A receptor-mediated tonic inhibition are providing unique new therapeutic approaches for epilepsy, status epilepticus, and certain brain disorders. The discovery of an extrasynaptic molecular mechanism represents a milestone for developing novel therapies such as NS replacement therapy for catamenial epilepsy.

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The GABAA Receptor γ2 Subunit (R43Q) Mutation in Febrile Seizures

Cited by 7 publications

References 28 publications

Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner

Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner

Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach

Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy

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