Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

Stödberg, T. and McTague, A. and Ruiz, A.J. and Hirata, H. and Zhen, J. and Long, P. and Farabella, Irene and Meyer, E. and Kawahara, A. and Vassallo, G. and Stivaros, S.M. and Bjursell, M.K. and Stranneheim, H. and Tigerschiöld, S. and Persson, B. and Bangash, I. and Das, K. and Hughes, D. and Lesko, N. and Lundeberg, J. and Scott, R.C. and Poduri, A. and Scheffer, I.E. and Smith, H. and Gissen, P. and Schorge, S. and Reith, M.E.A. and Topf, Maya and Kullmann, D.M. and Harvey, R.J. and Wedell, A. and Kurian, M.A. (2015) Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nature Communications 6 , p. 8038. ISSN 2041-1723.

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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