TITLE

De novo GABRG2 mutations associated with epileptic encephalopathies

AUTHOR(S)
Dingding Shen; Hernandez, Ciria C.; Wangzhen Shen; Ningning Hu; Poduri, Annapurna; Shiedley, Beth; Rotenberg, Alex; Datta, Alexandre N.; Leiz, Steffen; Patzer, Steffi; Boor, Rainer; Ramsey, Kerri; Goldberg, Ethan; Helbig, Ingo; Ortiz-Gonzalez, Xilma R.; Lemke, Johannes R.; Marsh, Eric D.; Macdonald, Robert L.; Shen, Dingding; Shen, Wangzhen
PUB. DATE
January 2017
SOURCE
Brain: A Journal of Neurology;Jan2017, Vol. 140 Issue 1, p49
SOURCE TYPE
Academic Journal
DOC. TYPE
journal article
ABSTRACT
Epileptic encephalopathies are a devastating group of severe childhood onset epilepsies with medication-resistant seizures and poor developmental outcomes. Many epileptic encephalopathies have a genetic aetiology and are often associated with de novo mutations in genes mediating synaptic transmission, including GABAA receptor subunit genes. Recently, we performed next generation sequencing on patients with a spectrum of epileptic encephalopathy phenotypes, and we identified five novel (A106T, I107T, P282S, R323W and F343L) and one known (R323Q) de novo GABRG2 pathogenic variants (mutations) in eight patients. To gain insight into the molecular basis for how these mutations contribute to epileptic encephalopathies, we compared the effects of the mutations on the properties of recombinant α1β2γ2L GABAA receptors transiently expressed in HEK293T cells. Using a combination of patch clamp recording, immunoblotting, confocal imaging and structural modelling, we characterized the effects of these GABRG2 mutations on GABAA receptor biogenesis and channel function. Compared with wild-type α1β2γ2L receptors, GABAA receptors containing a mutant γ2 subunit had reduced cell surface expression with altered subunit stoichiometry or decreased GABA-evoked whole-cell current amplitudes, but with different levels of reduction. While a causal role of these mutations cannot be established directly from these results, the functional analysis together with the genetic information suggests that these GABRG2 variants may be major contributors to the epileptic encephalopathy phenotypes. Our study further expands the GABRG2 phenotypic spectrum and supports growing evidence that defects in GABAergic neurotransmission participate in the pathogenesis of genetic epilepsies including epileptic encephalopathies.
ACCESSION #
120486162

 

Related Articles

  • Glutamate Transporters EAAT4 and EAAT5 Are Expressed in Vestibular Hair Cells and Calyx Endings. Dalet, Antoine; Bonsacquet, Jérémie; Gaboyard-Niay, Sophie; Calin-Jageman, Irina; Chidavaenzi, Robstein L.; Venteo, Stephanie; Desmadryl, Gilles; Goldberg, Jay M.; Lysakowski, Anna; Chabbert, Christian; Riley, Bruce // PLoS ONE;Sep2012, Vol. 7 Issue 9, Special section p1 

    Glutamate is the neurotransmitter released from hair cells. Its clearance from the synaptic cleft can shape neurotransmission and prevent excitotoxicity. This may be particularly important in the inner ear and in other sensory organs where there is a continually high rate of neurotransmitter...

  • Nicotinic receptor/ionic channel complex (AChR) in androgen-dependent skeletal muscle cultures. Bielavsky, M.; Souccar, C.; Lapa, A. J.; Lima-Landman, M. T. R. // Pflugers Archiv European Journal of Physiology;Feb2002, Vol. 443 Issue 4, p595 

    The kinetic properties of the nicotinic receptor/ionic channel complex (AChR) were compared in cell cultures obtained from androgen-dependent skeletal muscles of the perineal complex (P) and from muscles less dependent upon sex hormones (the thigh musculature, T). Because the development of P is...

  • Timing and efficacy of transmitter release at mossy fiber synapses in the hippocampal network. Bischofberger, Josef; Engel, Dominique; Frotscher, Michael; Jonas, Peter // Pflugers Archiv European Journal of Physiology;Dec2006, Vol. 453 Issue 3, p361 

    It is widely accepted that the hippocampus plays a major role in learning and memory. The mossy fiber synapse between granule cells in the dentate gyrus and pyramidal neurons in the CA3 region is a key component of the hippocampal trisynaptic circuit. Recent work, partially based on direct...

  • The inhibitory effect of angiotensin II on BK channels in podocytes via oxidative stress. Gao, Na; Zhang, Xiaochen; Yang, Zhuo; Wang, Hui // Molecular & Cellular Biochemistry;Jan2015, Vol. 398 Issue 1/2, p217 

    Angiotensin II (Ang II) is an important active substance of the renin-angiotensin system (RAS). The present study has confirmed that abnormalities of Ang II may be related with cerebrovascular diseases, endocrine diseases, cardiovascular diseases, liver diseases, such as: cerebral hypoxia,...

  • Protonation of a histidine, H34, in kaliotoxin (KTX) is the reason for a better KTX block at low pH0.  // Pflugers Archiv European Journal of Physiology;Apr2000 Supplement, Vol. 439, pR305 

    An abstract of the article "Protonation of a Histidine, H34, in Kaliotoxin (KTX) is the Reason for a Better KTX Block at Low pH0," by A. Wrisch and S. Grissmer is presented. This study examines the pH0-dependence of KTX block on Kv1.1 and H404T mutant Kv1.3 channels through the use of the whole...

  • Differential sensitivity of GABAergic and glycinergic inputs to orexin-A in preganglionic cardiac vagal neurons of newborn rats. Ji-jiang Wang; Yong-hua Chen; Ke-yong Li; Feng-Yan Sun // Acta Pharmacologica Sinica;Dec2005, Vol. 26 Issue 12, p1442 

    Aim: To test the effect of orexin-A (hypocretin-1), a neuropeptide synthesized in the lateral hypothalamus and the perifornical area, on the glycinergic inputs and the GABAergic inputs of cardiac vagal neurons (CVN). Methods: The effects of orexin-A at three concentrations (20 nmol/L, 100...

  • N-Arachidonoyl-Dopamine Tunes Synaptic Transmission onto Dopaminergic Neurons by Activating both Cannabinoid and Vanilloid Receptors. Marinelli, Silvia; Di Marzo, Vincenzo; Florenzano, Fulvio; Fezza, Filomena; Viscomi, Maria Teresa; van der Stelt, Mario; Bernardi, Giorgio; Molinari, Marco; Maccarrone, Mauro; Mercuri, Nicola B. // Neuropsychopharmacology;Feb2007, Vol. 32 Issue 2, p298 

    In the present study, we used electrophysiological, biochemical, and confocal microscopy techniques, to investigate the functional role of transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid type 1 receptors (CB1-R) in the substantia nigra pars compacta (SNpc) and their...

  • Voltage-gated Inward Currents of Morphologically Identified Cells of the Frog Taste Disc. Suwabe, Takeshi; Kitada, Yasuyuki // Chemical Senses;Jan2004, Vol. 29 Issue 1, p61 

    We used the patch clamp technique to record from taste cells in vertical slices of the bullfrog (Rana catesbeiana) taste disc. Cell types were identified by staining with Lucifer yellow in a pipette after recording their electrophysiological properties. Cells could be divided into the following...

  • Disordered Migration of Interneurons within Focal Cortical Dysplasia. Kapur, Jaideep // Epilepsy Currents;May-Jun2006, Vol. 6 Issue 3, p96 

    The article examines a study that investigated gamma-aminobutyric acid-receptor-mediated synaptic inhibition in regions of focal cortical dysplasia (FCD) using whole-cell patch-clamp recordings from identified neurons. The nature of FCD is discussed. The effect of the alterations on the process...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics