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.
Highlights
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
Epilepsy of infancy with migrating focal seizures (EIMFS) is an early-infantile epileptic encephalopathy (EIEE) previously known as migrating partial seizures of infancy. It is characterized by multifocal seizures, developmental arrest or regression and a distinct ictal pattern on electroencephalogram (EEG)[1,2]
We demonstrate that the identified mutants negatively impact KCC2 protein expression and glycosylation, with impaired KCC2-mediated chloride extrusion
Summary
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. 17 Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden. We report a novel genetic cause of EIMFS, identifying recessive SLC12A5 mutations in four affected children from two unrelated families.
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