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Sci Rep. 2016 Jul 20;6:30072. doi: 10.1038/srep30072.

Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay.

Author information

1
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Yokohama 236-0004, Japan.
2
Department of Neurophysiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
3
Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan.
4
Department of Genetics, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur 50586, Malaysia.
5
Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Sapporo 060-8638, Japan.
6
Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
7
Department of Pediatrics, Institute of Pediatrics, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur 50586, Malaysia.
8
Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Nagoya 467-8601, Japan.
9
Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan.

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.

PMID:
27436767
PMCID:
PMC4951812
DOI:
10.1038/srep30072
[Indexed for MEDLINE]
Free PMC Article

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