Dataset Information

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

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.

SUBMITTER: Stodberg T

PROVIDER: S-EPMC4569694 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

Stödberg Tommy T McTague Amy A Ruiz Arnaud J AJ Hirata Hiromi H Zhen Juan J Long Philip P Farabella Irene I Meyer Esther E Kawahara Atsuo A Vassallo Grace G Stivaros Stavros M SM Bjursell Magnus K MK Stranneheim Henrik H Tigerschiöld Stephanie S Persson Bengt B Bangash Iftikhar I Das Krishna K Hughes Deborah D Lesko Nicole N Lundeberg Joakim J Scott Rod C RC Poduri Annapurna A Scheffer Ingrid E IE Smith Holly H Gissen Paul P Schorge Stephanie S Reith Maarten E A ME Topf Maya M Kullmann Dimitri M DM Harvey Robert J RJ Wedell Anna A Kurian Manju A MA

Nature communications 20150903

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 ...[more]

PMID: 26333769

Similar Datasets

Project description:SCN2A encodes a voltage-gated sodium channel (NaV1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in SCN2A are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss-of-function variants typically being associated with neurodevelopmental delay and later-onset seizures, whereas gain-of-function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing SCN2A variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in SCN2A. Voltage-clamp studies of the variant expressed on adult and neonatal NaV1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss-of-function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage dependence of activation and an increase in the voltage dependence of inactivation. This finding of a predominantly loss-of-function effect was unexpected, as the infant's early epilepsy onset would have suggested a predominantly gain-of-function effect. This case illustrates that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.NEW & NOTEWORTHY Voltage-gated sodium channels play an important role in the central nervous system, mutations in which have been reported to be responsible for epilepsy. We report here an infant presenting with epilepsy of infancy with migrating focal seizures (EIMFS) in the neonatal period with a mosaic c.2635G>A, resulting in a p.Gly879Arg missense mutation on the SCN2A gene encoding NaV1.2 sodium channels. Biophysical characterization of this variant revealed a mixture of gain- and loss-of-function effects.

Dataset Information

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

Publications

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets