Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.
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.
Department of Women's and Children's Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden.|Neuropediatric Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Tommy
T
Stödberg
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.|Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Amy
A
McTague
Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
Arnaud J
AJ
Ruiz
Department of Chemistry and Biological Science, Graduate School of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258 Kanagawa, Japan.|Center for Frontier Research, National Institute of Genetics, Yata 1111, Mishima, 411-8540 Shizuoka, Japan.|PREST, Japan Science and Technology Agency, Tokyo 102-0076, Japan.
Hiromi
H
Hirata
Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA.
Juan
J
Zhen
Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
Philip
P
Long
Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, WC1E 7HX, UK.
Irene
I
Farabella
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
Esther
E
Meyer
Laboratory for Developmental Biology, Graduate School of Medical Science, University of Yamanashi, Chuo, 409-3898, Japan.
Atsuo
A
Kawahara
Department of Neurology, Royal Manchester Children's Hospital, Manchester, M13 9WL, UK.
Grace
G
Vassallo
Academic Department of Radiology, Royal Manchester Children's Hospital, Manchester, M13 9WL, UK.|Imaging Science, School of Population Health, University of Manchester, Manchester, M13 9PL, UK.
Stavros M
SM
Stivaros
Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Magnus K
MK
Bjursell
Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.|Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Henrik
H
Stranneheim
Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.|Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Stephanie
S
Tigerschiöld
Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.|Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, SE-171 21 Stockholm, Sweden.
Bengt
B
Persson
EEG Department, Royal Oldham Hospital, OL1 2JH, Oldham, Lancashire, UK.
Iftikhar
I
Bangash
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.|Young Epilepsy, RH7 6PW, Lingfield, Surrey, UK.
Krishna
K
Das
Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG, London, UK.
Deborah
D
Hughes
Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.|Department of Laboratory Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Nicole
N
Lesko
Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology, SE-100 44 Stockholm, Sweden.
Joakim
J
Lundeberg
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.|Department of Neurological Sciences, University of Vermont College of Medicine, Vermont, VT 05405, USA.|Department of Paediatric Neurology, Fletcher Allen Health Care, Vermont, VT 05401, USA.|Clinical Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London, WC1N 1EH, London, UK.
Rod C
RC
Scott
Department of Neurology, Epilepsy Genetics Programme, Boston Children's Hospital, Boston, Massachusetts, Massachusetts 02115, USA.|Department of Neurology, Harvard Medical School, Boston, Massachusetts, Massachusetts 02115, USA.
Annapurna
A
Poduri
Department of Medicine and Paediatrics, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, VIC 3052, Australia.|Florey Institute, Melbourne, Victoria, VIC 3010, Australia.
Ingrid E
IE
Scheffer
MRC Laboratory for Molecular Cell Biology, UCL, London, WC1E 6BT, UK.
Holly
H
Smith
MRC Laboratory for Molecular Cell Biology, UCL, London, WC1E 6BT, UK.|Department of Metabolic Medicine, Great Ormond Street Hospital, London, WC1N 3JH, UK.|Genetics and Genomic Medicine, Institute of Child Health, UCL, London, WC1N 1EH, UK.
Paul
http://orcid.org/0000-0002-9712-6122
P
Gissen
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
Stephanie
S
Schorge
Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Maarten E A
ME
Reith
Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, WC1E 7HX, UK.
Maya
M
Topf
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
Dimitri M
DM
Kullmann
Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
Robert J
RJ
Harvey
Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.|Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Anna
A
Wedell
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.|Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Manju A
MA
Kurian
D000818:Animals; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism*; D004828:Epilepsies, Partial / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D008297:Male; D009154:Mutation; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017422:Sequence Analysis, DNA; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins; D000096922:K Cl- Cotransporters
D002712:Chlorides; D027981:Symporters; D029961:Zebrafish Proteins; D000096922:K Cl- Cotransporters; C000606816:SLC12A5 protein, human