Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
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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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- Authors
- Stödberg, T., McTague, A., Ruiz, A. J., Hirata, H., Zhen, J., Long, P., Farabella, I., Meyer, E., Kawahara, A., Vassallo, G., Stivaros, S. M., Bjursell, M. K., Stranneheim, H., Tigerschiöld, S., Persson, B., Bangash, I., Das, K., Hughes, D., Lesko, N., Lundeberg, J., Scott, R. C., Poduri, A., Scheffer, I. E., Smith, H., Gissen, P., Schorge, S., Reith, M. E. A., Topf, M., Kullmann, D. M., Harvey, R. J., Wedell, A., & Kurian, M. A.
- Affiliations
- Karolinska University Hospital (SE)
- Great Ormond Street Hospital (GB)
- UCL School of Pharmacy (GB)
- National Institute of Genetics (JP)
- New York University (US)
- Institute of Structural and Molecular Biology (GB)
- University College London (GB)
- University of Yamanashi (JP)
- Royal Manchester Children's Hospital (GB)
- University of Manchester (GB)
- Science for Life Laboratory (SE)
- Uppsala University (SE)
- Royal Oldham Hospital (GB)
- UCL Queen Square Institute of Neurology (GB)
- University of Vermont (US)
- Boston Children's Hospital (US)
- Royal Children's Hospital (AU)
- MRC Laboratory for Molecular Cell Biology (GB)
- Corresponding author
- Wedell, Anna
- Kurian, Manju A.
- ORCID
- Stödberg, Tommy
- McTague, Amy
- Ruiz, Arnaud J.
- Hirata, Hiromi
- Zhen, Juan
- Farabella, Irene
- Meyer, Esther
- Kawahara, Atsuo
- Vassallo, Grace
- Stivaros, Stavros M.
- Bjursell, Magnus K.
- Stranneheim, Henrik
- Bangash, Iftikhar
- Das, Krishna
- Lesko, Nicole
- Lundeberg, Joakim
- Scott, Rod C.
- Poduri, Annapurna
- Scheffer, Ingrid E.
- Gissen, Paul
- Reith, Maarten E. A.
- Topf, Maya
- Kullmann, Dimitri M.
- Kurian, Manju A.
- Venue
- Nature Communications
- Published
- 2015-09-03
- Volume
- 6
- Issue
- 1
- Pages
- 8038-8038
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4569694
- OpenAlex
- W1922290279
- Cited by
- 184
- References
- 38
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 10 · 2023: 12 · 2022: 19 · 2021: 15 · 2020: 30 · 2019: 22 · 2018: 18 · 2017: 16 · 2016: 17 · 2015: 1
- FWCI
- 14.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BIROn (Birkbeck, University of London) (acceptedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Takeda Science Foundation
- Wellcome Trust (095662, 104033, 104033/Z/14/Z, 095580)
- Action Medical Research
- National Institute for Health and Care Research (NIHR/CS/010/021)
- Leverhulme Trust (BB/K01692X/1, RPG-2012-519)
- Ministry of Education, Culture, Sports, Science and Technology
- Inamori Foundation
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Stockholms Läns Landsting
- Vetenskapsrådet (12198)
- National Institutes of Health (DA019676)
- Medical Research Council (MR/M013502/1, MR/J004049/1, MR/L003457/1, MR/L01095X/1, MR/L001497/1, J004049, MR/K000608/1)
- Biotechnology and Biological Sciences Research Council (BB/K01692X/1)
- Japan Society for the Promotion of Science (15K14373, 25290008)
- National Institute on Drug Abuse (DA019676, R01DA019676)
- National Institute of Neurological Disorders and Stroke (K23NS069784)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- KCC2, epilepsy of infancy with migrating focal seizures, loss-of-function mutations, recessive inheritance, drug-resistant epilepsy, chloride extrusion, protein glycosylation, synaptic inhibition, neuronal excitability, epileptic encephalopathy, monogenic epilepsy
- MeSH terms
- K Cl- Cotransporters, Animals, Child, Child, Preschool, Chlorides, Epilepsies, Partial, Humans, Infant, Male, Mutation, Neural Inhibition, Neurons, Pedigree, Zebrafish, Immunoblotting, Sequence Analysis, DNA, Patch-Clamp Techniques, Symporters, Zebrafish Proteins, HEK293 Cells
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