title: A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes.
abstract: Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS+). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS+ and screened for variations in the γ2 subunit of the γ-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136*) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and extended behavioural presentation. The GABRG2(p.R136*) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that γ2(p.R136*) subunits were produced, but had reduced cell-surface and total expression. When γ2(p.R136*) subunits were co-expressed with α1 and β2 subunits in HEK 293T cells, GABA-evoked currents were reduced. Furthermore, γ2(p.R136*) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136*) mutation extends the spectrum of GABRG2 mutations identified in GEFS+ and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism.
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4X, UK.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Johnston
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA.
authors.forename: Jing-Qiong
authors.initials: JQ
authors.lastname: Kang
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA.
authors.forename: Wangzhen
authors.initials: W
authors.lastname: Shen
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4X, UK.
authors.forename: William O
authors.initials: WO
authors.lastname: Pickrell
authors.affiliation: Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Cushion
authors.affiliation: Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Davies
authors.affiliation: Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Kristin
authors.initials: K
authors.lastname: Baer
authors.affiliation: Genome and Structural Bioinformatics, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Jonathan G L
authors.initials: JGL
authors.lastname: Mullins
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Hammond
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Seo-Kyung
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4X, UK.
authors.forename: Rhys H
authors.initials: RH
authors.lastname: Thomas
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Paediatric Neurology, Singleton Hospital, Abertawe Bro-Morgannwg University Health Board, Swansea SA2 8PP, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4X, UK.
authors.forename: Phil E M
authors.initials: PEM
authors.lastname: Smith
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Macdonald
authors.affiliation: Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.|Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D004829:Epilepsy, Generalized / Q000235:genetics*; D005190:Family; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D009474:Neurons / Q000502:physiology; D016716:PC12 Cells; D010641:Phenotype; D017354:Point Mutation; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D003294:Seizures, Febrile / Q000235:genetics*
chemical_list: C546279:GABRG2 protein, human; D011963:Receptors, GABA-A
keywords: Epilepsy; GABAA receptors; Protein truncating mutations; Receptor trafficking