ArticleNature communications2015
Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.
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Article in Nature communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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92citing papers in PubMed
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92 citing papers in PubMed, 177 citations in OpenAlex.
- Regulated degradation of KCC2, a potassium-chloride co-transporter required for synaptic transmission and neurodevelopment.Channels (Austin, Tex.) · 2026Review
- Solute carrier membrane transporters: emerging targets in CNS disorders.Nature reviews. Drug discovery · 2026Review
- The Mechanism of Long Non-coding RNA GABPB1-AS1/SLC12A5 Regulating Neuronal Ferroptosis in Epileptic Seizures.Neurochemical research · 2026Article
- Abnormal KCC2 expression and function in a mouse model of epilepsy and tuberous sclerosis complex.Epilepsia · 2026Article
- Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures.The Journal of clinical investigation · 2026Article
- Compound heterozygous SLC12A5 variants expand the molecular and functional spectrum of KCC2-developmental and epileptic encephalopathy.Epilepsia · 2026Article
- Structural basis for the ion selectivity of potassium-chloride cotransporter KCC4 revealed by cryo-EM titration.Biophysics reports · 2026Article
- Downregulation of SLC12A5 in glioblastoma multiforme: a novel prognostic biomarker associated with brain edema and radiomic features.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation.Genome medicine · 2026Article
- Neuro-Transcriptomic Responses to Polypharmacological Agents inBrain sciences · 2026Article
- KCC2 activation during postnatal development alleviates long-term deficits in CDKL5-deficient mice.Experimental & molecular medicine · 2026Article
- The effect of human-specific genetic variants on neuronal spinogenesis.Frontiers in genetics · 2026Review
- Diverse species of animal models in epilepsy research: Progress and perspectives.Zoological research · 2025Review
- Clinical whole genome sequencing in pediatric epilepsy: Genetic and phenotypic spectrum of 733 individuals.Epilepsia · 2025Article
- Epilepsy of Infancy With Migrating Focal Seizures.Annals of the Child Neurology Society · 2025Article
- Highly conserved ion binding sites are not all functionally relevant in mouse KCC4.Frontiers in molecular biosciences · 2025Article
- Genetic aetiologies in relation to response to the ketogenic diet in 226 children with epilepsy.Brain communications · 2025Article
- KCC2 inhibition and neuronal hyperexcitability promote extrinsic apoptosis dependent upon C1q.Frontiers in molecular neuroscience · 2025Article
- Expanding the clinical and genetic landscape of (developmental) epileptic encephalopathy with spike-and-wave activation in sleep: results from studies of a Turkish cohort.Neurogenetics · 2024Article
- The expression system influences stability, maturation efficiency, and oligomeric properties of the potassium-chloride co-transporter KCC2.Neurochemistry international · 2024Article
32 more citing papers are in PubMed but not listed here.
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Authors and funding
32 authors at 17 institutions in 6 countries.
Tommy StödbergDepartment of Women's and Children's Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Amy McTagueMolecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
Arnaud J RuizDepartment of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
Hiromi HirataDepartment of Chemistry and Biological Science, Graduate School of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258 Kanagawa, Japan.
Juan ZhenDepartment of Psychiatry, New York University School of Medicine, New York, New York 10016, USA.
Philip LongDepartment of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
Irene FarabellaInstitute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, WC1E 7HX, UK.
Esther MeyerMolecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
Atsuo KawaharaLaboratory for Developmental Biology, Graduate School of Medical Science, University of Yamanashi, Chuo, 409-3898, Japan.
Grace VassalloDepartment of Neurology, Royal Manchester Children's Hospital, Manchester, M13 9WL, UK.
Stavros M StivarosAcademic Department of Radiology, Royal Manchester Children's Hospital, Manchester, M13 9WL, UK.
Magnus K BjursellDepartment of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Henrik StranneheimDepartment of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Stephanie TigerschiöldDepartment of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Bengt PerssonDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
Iftikhar BangashEEG Department, Royal Oldham Hospital, OL1 2JH, Oldham, Lancashire, UK.
Krishna DasDepartment of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Deborah HughesDepartment of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG, London, UK.
Nicole LeskoCentre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Joakim LundebergScience for Life Laboratory, School of Biotechnology, Royal Institute of Technology, SE-100 44 Stockholm, Sweden.
Rod C ScottDepartment of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Annapurna PoduriDepartment of Neurology, Epilepsy Genetics Programme, Boston Children's Hospital, Boston, Massachusetts, Massachusetts 02115, USA.
Ingrid E SchefferDepartment of Medicine and Paediatrics, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, VIC 3052, Australia.
Holly SmithMRC Laboratory for Molecular Cell Biology, UCL, London, WC1E 6BT, UK.
Paul GissenMRC Laboratory for Molecular Cell Biology, UCL, London, WC1E 6BT, UK.ORCID http://orcid.org/0000-0002-9712-6122
Stephanie SchorgeDepartment of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
Maarten E A ReithDepartment of Psychiatry, New York University School of Medicine, New York, New York 10016, USA.
Maya TopfInstitute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, WC1E 7HX, UK.
Dimitri M KullmannDepartment of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
Robert J HarveyDepartment of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
Anna WedellDepartment of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Manju A KurianMolecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
Karolinska University Hospital · SEUniversity College London · GBGreat Ormond Street Hospital · GBInstitute of Structural and Molecular Biology · GBNew York University · USScience for Life Laboratory · SEBoston Children's Hospital · USInstitute of Child Health · INMRC Laboratory for Molecular Cell Biology · GBNational Institute of Genetics · JPRoyal Children's Hospital · AURoyal Manchester Children's Hospital · GBRoyal Oldham Hospital · GBUniversity of Manchester · GBUniversity of Vermont · USUniversity of Yamanashi · JPUppsala University · SE
Funding
Dopamine Transporters: Mechanisms of Ligand InteractionR01DA019676 · NIDA · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI REITH, MAARTEN E · 2006 to 2016
$2.9MGenetics of Familial Epilepsy SyndromesK23NS069784 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI PODURI, ANNAPURNA · 2010 to 2014
$901kBiotechnology and Biological Sciences Research Council BB/K01692X/1Department of Health NIHR/CS/010/021Medical Research Council G0200373Medical Research Council G0801316Medical Research Council G0802158Medical Research Council G116/147Medical Research Council MR/J004049/1Medical Research Council MR/L001497/1Medical Research Council MR/L003457/1Medical Research Council MR/L01095X/1Medical Research Council MR/M013502/1NIDA NIH HHS DA019676NIDA NIH HHS R01 DA019676NINDS NIH HHS K23 NS069784NINDS NIH HHS K23NS069784Wellcome Trust 095580Wellcome Trust 095662Wellcome Trust 104033
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.
Indexed as
AnimalsChildChild, PreschoolChloridesEpilepsies, PartialHEK293 CellsHumansImmunoblottingInfantK Cl- CotransportersMaleMutationNeural InhibitionNeuronsPatch-Clamp TechniquesPedigreeChloridesK Cl- CotransportersSLC12A5 protein, humanSymportersZebrafish Proteins
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