2. Academic Validation
  3. Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

  • Nat Commun. 2015 Sep 3;6:8038. doi: 10.1038/ncomms9038.
Tommy Stödberg 1 2,  Amy McTague 3 4,  Arnaud J Ruiz 5,  Hiromi Hirata 6 7 8,  Juan Zhen 9,  Philip Long 5,  Irene Farabella 10,  Esther Meyer 3,  Atsuo Kawahara 11,  Grace Vassallo 12,  Stavros M Stivaros 13 14,  Magnus K Bjursell 15,  Henrik Stranneheim 15 16,  Stephanie Tigerschiöld 15 16,  Bengt Persson 17 18,  Iftikhar Bangash 19,  Krishna Das 4 20,  Deborah Hughes 21,  Nicole Lesko 16 22,  Joakim Lundeberg 23,  Rod C Scott 4 24 25 26,  Annapurna Poduri 27 28,  Ingrid E Scheffer 29 30,  Holly Smith 31,  Paul Gissen 31 32 33,  Stephanie Schorge 34,  Maarten E A Reith 9 35,  Maya Topf 10,  Dimitri M Kullmann 34,  Robert J Harvey 5,  Anna Wedell 15 16,  Manju A Kurian 3 4
Affiliations

Affiliations

  • 1 Department of Women's and Children's Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
  • 2 Neuropediatric Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
  • 3 Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
  • 4 Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • 5 Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
  • 6 Department of Chemistry and Biological Science, Graduate School of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258 Kanagawa, Japan.
  • 7 Center for Frontier Research, National Institute of Genetics, Yata 1111, Mishima, 411-8540 Shizuoka, Japan.
  • 8 PREST, Japan Science and Technology Agency, Tokyo 102-0076, Japan.
  • 9 Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA.
  • 10 Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, WC1E 7HX, UK.
  • 11 Laboratory for Developmental Biology, Graduate School of Medical Science, University of Yamanashi, Chuo, 409-3898, Japan.
  • 12 Department of Neurology, Royal Manchester Children's Hospital, Manchester, M13 9WL, UK.
  • 13 Academic Department of Radiology, Royal Manchester Children's Hospital, Manchester, M13 9WL, UK.
  • 14 Imaging Science, School of Population Health, University of Manchester, Manchester, M13 9PL, UK.
  • 15 Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
  • 16 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
  • 17 Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
  • 18 Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, SE-171 21 Stockholm, Sweden.
  • 19 EEG Department, Royal Oldham Hospital, OL1 2JH, Oldham, Lancashire, UK.
  • 20 Young Epilepsy, RH7 6PW, Lingfield, Surrey, UK.
  • 21 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG, London, UK.
  • 22 Department of Laboratory Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
  • 23 Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology, SE-100 44 Stockholm, Sweden.
  • 24 Department of Neurological Sciences, University of Vermont College of Medicine, Vermont, VT 05405, USA.
  • 25 Department of Paediatric Neurology, Fletcher Allen Health Care, Vermont, VT 05401, USA.
  • 26 Clinical Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London, WC1N 1EH, London, UK.
  • 27 Department of Neurology, Epilepsy Genetics Programme, Boston Children's Hospital, Boston, Massachusetts, Massachusetts 02115, USA.
  • 28 Department of Neurology, Harvard Medical School, Boston, Massachusetts, Massachusetts 02115, USA.
  • 29 Department of Medicine and Paediatrics, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, VIC 3052, Australia.
  • 30 Florey Institute, Melbourne, Victoria, VIC 3010, Australia.
  • 31 MRC Laboratory for Molecular Cell Biology, UCL, London, WC1E 6BT, UK.
  • 32 Department of Metabolic Medicine, Great Ormond Street Hospital, London, WC1N 3JH, UK.
  • 33 Genetics and Genomic Medicine, Institute of Child Health, UCL, London, WC1N 1EH, UK.
  • 34 Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
  • 35 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
PMID: 26333769 DOI: 10.1038/ncomms9038
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.

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