Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay
Copyright policy )Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay
AbstractEpilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic syndromes characterized by migrating polymorphous focal seizures. Whole exome sequencing (WES) in ten sporadic and one familial case of EIMFS revealed compound heterozygous SLC12A5 (encoding the neuronal K+-Cl− co-transporter KCC2) mutations in two families: c.279 + 1G > C causing skipping of exon 3 in the transcript (p.E50_Q93del) and c.572 C >T (p.A191V) in individuals 1 and 2, and c.967T > C (p.S323P) and c.1243 A > G (p.M415V) in individual 3. Another patient (individual 4) with migrating multifocal seizures and compound heterozygous mutations [c.953G > C (p.W318S) and c.2242_2244del (p.S748del)] was identified by searching WES data from 526 patients and SLC12A5-targeted resequencing data from 141 patients with infantile epilepsy. Gramicidin-perforated patch-clamp analysis demonstrated strongly suppressed Cl− extrusion function of E50_Q93del and M415V mutants, with mildly impaired function of A191V and S323P mutants. Cell surface expression levels of these KCC2 mutants were similar to wildtype KCC2. Heterologous expression of two KCC2 mutants, mimicking the patient status, produced a significantly greater intracellular Cl− level than with wildtype KCC2, but less than without KCC2. These data clearly demonstrated that partially disrupted neuronal Cl− extrusion, mediated by two types of differentially impaired KCC2 mutant in an individual, causes EIMFS.
- Hokkaido Bunkyo University Japan
- Showa University Japan
- Hospital Kuala Lumpur Malaysia
- Nagoya City University Japan
- Hokkaido University Japan
Adult, Male, Exome sequencing, Molecular Mechanisms of Synaptic Plasticity and Neurological Disorders, Molecular biology, Heterozygote advantage, Wild type, Exon, Polymorphism, Single Nucleotide, Gene, Article, Young Adult, Cellular and Molecular Neuroscience, Chlorides, Seizures, Biochemistry, Genetics and Molecular Biology, Health Sciences, Genetics, Humans, Status epilepticus, Biology, Sequence Deletion, Allele, Compound heterozygosity, Epilepsy, Symporters, Mechanisms of Multidrug Resistance in Cancer, Neurotransmission, Mutant, Infant, Life Sciences, Biological Transport, Intracellular, K Cl- Cotransporters, Oncology, Child, Preschool, FOS: Biological sciences, Mutation, Medicine, Molecular Basis of Rett Syndrome and Related Disorders, Female, Neuroscience
Adult, Male, Exome sequencing, Molecular Mechanisms of Synaptic Plasticity and Neurological Disorders, Molecular biology, Heterozygote advantage, Wild type, Exon, Polymorphism, Single Nucleotide, Gene, Article, Young Adult, Cellular and Molecular Neuroscience, Chlorides, Seizures, Biochemistry, Genetics and Molecular Biology, Health Sciences, Genetics, Humans, Status epilepticus, Biology, Sequence Deletion, Allele, Compound heterozygosity, Epilepsy, Symporters, Mechanisms of Multidrug Resistance in Cancer, Neurotransmission, Mutant, Infant, Life Sciences, Biological Transport, Intracellular, K Cl- Cotransporters, Oncology, Child, Preschool, FOS: Biological sciences, Mutation, Medicine, Molecular Basis of Rett Syndrome and Related Disorders, Female, Neuroscience
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