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Brain. 2017 Jan;140(1):49-67. doi: 10.1093/brain/aww272. Epub 2016 Nov 17.

De novo GABRG2 mutations associated with epileptic encephalopathies.

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1 The Graduate Program of Neuroscience, Vanderbilt University, Nashville, TN 37232, USA.
2 Department of Neurology, Vanderbilt University, Nashville, TN 37240, USA.
3 Epilepsy Genetics Program and the Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
4 Harvard Medical School, Boston, MA 02115, USA.
5 Division of Pediatric Neurology and Developmental Medicine, University of Basel Children's Hospital, Basel 4056, Switzerland.
6 Clinic for Children and Adolescents Dritter Orden, Divison of Neuropediatrics, München, 80638 Germany.
7 Clinic for Children and Adolescents, Halle/Saale, 06097 Germany.
8 Department of Pediatric Neurology, Kiel University, Kiel 24118 Germany; Northern German Epilepsy Centre for Children and Adolescents, Schwentinental - Raisdorf, 24223 Germany.
9 Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, 85004 AZ, USA.
10 Departments of Neurology and Paediatrics, Division of Child Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
11 Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
12 Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, 04103 Germany.
2 Department of Neurology, Vanderbilt University, Nashville, TN 37240, USA


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.


GABAA receptor; GABRG2; de novo mutation; epileptic encephalopathy; next generation sequencing

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