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Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Neuropediat Unit, SE-17176 Stockholm, Sweden..
UCL Inst Child Hlth, Dev Neurosci Programme, Mol Neurosci, London WC1N 1EH, England.;Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England..
UCL Sch Pharm, Dept Pharmacol, London WC1N 1AX, England..
Aoyama Gakuin Univ, Grad Sch Sci & Engn, Dept Chem & Biol Sci, Sagamihara, Kanagawa 2525258, Japan.;Natl Inst Genet, Ctr Frontier Res, Mishima, Shizuoka 4118540, Japan.;Japan Sci & Technol Agcy, PREST, Tokyo 1020076, Japan..
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2015 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, 8038Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 6, 8038
National Category
Pediatrics Cell and Molecular Biology
URN: urn:nbn:se:uu:diva-267073DOI: 10.1038/ncomms9038ISI: 000362945300001PubMedID: 26333769OAI: oai:DiVA.org:uu-267073DiVA: diva2:872961
EU, European Research CouncilSwedish Research Council, 12198Wellcome trustStockholm County CouncilKnut and Alice Wallenberg FoundationNIH (National Institute of Health)
Available from: 2015-11-20 Created: 2015-11-17 Last updated: 2015-11-20Bibliographically approved

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