title: Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.
abstract: GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ~4% of unsolved MAE cases.
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Gemma L
authors: GL
authors: Carvill
authors: Epilepsy Research Centre, Department of Medicine, University of Melbourne at Austin Health, Heidelberg, VIC 3084, Australia.
authors: Jacinta M
authors: JM
authors: McMahon
authors: Epilepsy Research Centre, Department of Medicine, University of Melbourne at Austin Health, Heidelberg, VIC 3084, Australia.
authors: Amy
authors: A
authors: Schneider
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Matthew
authors: M
authors: Zemel
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Candace T
authors: CT
authors: Myers
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Julia
authors: J
authors: Saykally
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: John
authors: J
authors: Nguyen
authors: Laboratory of Neurogenetics, Department of Neurosciences, Giannina Gaslini Institute, Genova 16148, Italy.
authors: Angela
authors: A
authors: Robbiano
authors: Laboratory of Neurogenetics, Department of Neurosciences, Giannina Gaslini Institute, Genova 16148, Italy.
authors: Federico
authors: F
authors: Zara
authors: Division of Neurology, Department of Neuroscience, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy.
authors: Nicola
authors: N
authors: Specchio
authors: Department of Neurology & Psychiatry, Sapienza University of Rome, Rome, Lazio 00185, Italy.
authors: Oriano
authors: O
authors: Mecarelli
authors: Department of Neurology, John Hunter Children's Hospital and University of Newcastle Faculty of Health, Newcastle, NSW 2305, Australia.
authors: Robert L
authors: RL
authors: Smith
authors: Department of Paediatrics, University of Melbourne and Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Neurology, Royal Children's Hospital, Parkville, VIC 3052, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors: Richard J
authors: RJ
authors: Leventer
authors: Danish Epilepsy Centre, 4293 Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense 5230, Denmark.
authors: Rikke S
authors: RS
authors: Møller
authors: Danish Epilepsy Centre, 4293 Dianalund, Denmark.
authors: Marina
authors: M
authors: Nikanorova
authors: Epilepsy Center, St. Ivan Rilski University Hospital, Sofia 1431, Bulgaria.
authors: Petia
authors: P
authors: Dimova
authors: Department of Molecular Genetics, Vlaams Instituut voor Biotechnologie, Antwerp 2610, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia 1431, Bulgaria.
authors: Albena
authors: A
authors: Jordanova
authors: Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3084, Australia.
authors: Steven
authors: S
authors: Petrou
authors: Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel Campus and Christian-Albrechts-University of Kiel, Kiel 24118, Germany.
authors: Ingo
authors: I
authors: Helbig
authors: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova and Giannina Gaslini Institute, Genova 16148, Italy.
authors: Pasquale
authors: P
authors: Striano
authors: Department of Molecular Genetics, Vlaams Instituut voor Biotechnologie, Antwerp 2610, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; INSERM U 1127, Centre National de la Recherche Scientifique UMR 7225, Université Pierre et Marie Curie (Paris 6) UMR S 1127, Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, Paris 75013, France.
authors: Sarah
authors: S
authors: Weckhuysen
authors: Epilepsy Research Centre, Department of Medicine, University of Melbourne at Austin Health, Heidelberg, VIC 3084, Australia.
authors: Samuel F
authors: SF
authors: Berkovic
authors: Epilepsy Research Centre, Department of Medicine, University of Melbourne at Austin Health, Heidelberg, VIC 3084, Australia; Department of Paediatrics, University of Melbourne and Royal Children's Hospital, Parkville, VIC 3052, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3084, Australia. Electronic address: scheffer@unimelb.edu.au.
authors: Ingrid E
authors: IE
authors: Scheffer
authors: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address: hmefford@uw.edu.
authors: Heather C
authors: HC
authors: Mefford
mesh_terms: D000818:Animals; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000473:pathology; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human