Abstract
Epilepsy 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.
Highlights
GABAA and glycine receptors that are responsible for the Cl− influx[8]
We focused on genes with two heterozygous variants or homozygous variants that were consistent with an autosomal-recessive trait, and found that SLC12A5 was a solo candidate
Three of the patients were diagnosed with Epilepsy of infancy with migrating focal seizures (EIMFS), and multifocal migrating seizures were observed in an additional patient
Summary
GABAA and glycine receptors that are responsible for the Cl− influx[8]. The presence of alternative first exons with different promoters provides two isoforms of KCC2a and KCC2b (see Fig. 1B). Heterozygous missense mutations in SLC12A5 were shown to be associated with febrile seizures and idiopathic generalized epilepsy in humans[12,13], and very recently, autosomal recessive SLC12A5 mutations were reported to cause EIMFS14. In the former two reports, the mutations were identified based only on the targeted DNA sequencing of SLC12A5, and possible causative mutations in other genes were not clearly excluded. Our data demonstrated that partial loss of neuronal KCC2 function by biallelic mutations might cause migrating focal seizures, which are characteristic of EIMFS
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