ZFIN ID: ZDB-PUB-170214-123
Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
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., Topf, M., Kullmann, D.M., Harvey, R.J., Wedell, A., Kurian, M.A.
Date: 2015
Source: Nature communications   6: 8038 (Journal)
Registered Authors: Hirata, Hiromi, Kawahara, Atsuo
Keywords: Disease genetics, Epilepsy, Glycosylation, Mutation
MeSH Terms:
  • Animals
  • Child
  • Child, Preschool
  • Chlorides/metabolism*
  • Epilepsies, Partial/genetics*
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Infant
  • Male
  • Mutation
  • Neural Inhibition/genetics*
  • Neurons/metabolism*
  • Patch-Clamp Techniques
  • Pedigree
  • Sequence Analysis, DNA
  • Symporters/genetics*
  • Symporters/metabolism
  • Zebrafish
  • Zebrafish Proteins
PubMed: 26333769 Full text @ Nat. Commun.
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.