Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

Tommy Stödberg, Amy McTague, Arnaud J. Ruiz, Hiromi Hirata, Juan Zhen, Philip Long, Irene Farabella, Esther Meyer, Atsuo Kawahara, Grace Vassallo, Stavros M. Stivaros, Magnus K. Bjursell, Henrik Stranneheim, Stephanie Tigerschiöld, Bengt Persson, Iftikhar Bangash, Krishna Das, Deborah Hughes, Nicole Lesko, Joakim Lundeberg, Rod C. Scott, Annapurna Poduri, Ingrid E. Scheffer, Holly Smith, Paul Gissen, Stephanie Schorge, Maarten E. A. Reith, Maya Topf, Dimitri M. Kullmann, Robert J. Harvey, Anna Wedell () and Manju A. Kurian ()
Additional contact information
Tommy Stödberg: Karolinska Institutet
Amy McTague: Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health
Arnaud J. Ruiz: UCL School of Pharmacy
Hiromi Hirata: Graduate School of Science and Engineering, Aoyama Gakuin University
Juan Zhen: New York University School of Medicine
Philip Long: UCL School of Pharmacy
Irene Farabella: Institute of Structural and Molecular Biology, Birkbeck College, University of London
Esther Meyer: Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health
Atsuo Kawahara: Laboratory for Developmental Biology, Graduate School of Medical Science, University of Yamanashi
Grace Vassallo: Royal Manchester Children’s Hospital
Stavros M. Stivaros: Royal Manchester Children’s Hospital
Magnus K. Bjursell: Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet
Henrik Stranneheim: Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet
Stephanie Tigerschiöld: Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet
Bengt Persson: Science for Life Laboratory, Uppsala University
Iftikhar Bangash: Royal Oldham Hospital
Krishna Das: Great Ormond Street Hospital
Deborah Hughes: UCL Institute of Neurology
Nicole Lesko: Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Joakim Lundeberg: Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology
Rod C. Scott: Great Ormond Street Hospital
Annapurna Poduri: Epilepsy Genetics Programme, Boston Children’s Hospital
Ingrid E. Scheffer: University of Melbourne, Austin Health and Royal Children’s Hospital
Holly Smith: MRC Laboratory for Molecular Cell Biology, UCL
Paul Gissen: MRC Laboratory for Molecular Cell Biology, UCL
Stephanie Schorge: UCL Institute of Neurology
Maarten E. A. Reith: New York University School of Medicine
Maya Topf: Institute of Structural and Molecular Biology, Birkbeck College, University of London
Dimitri M. Kullmann: UCL Institute of Neurology
Robert J. Harvey: UCL School of Pharmacy
Anna Wedell: Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet
Manju A. Kurian: Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy.

Date: 2015
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DOI: 10.1038/ncomms9038

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