A variant of KCC2 from patients with febrile seizures impairs neuronal Cl− extrusion and dendritic spine formation

• Published in: EMBO reports Vol. 15; no. 6; pp. 723 - 729
• Main Authors: Puskarjov, Martin, Seja, Patricia, Heron, Sarah E, Williams, Tristiana C, Ahmad, Faraz, Iona, Xenia, Oliver, Karen L, Grinton, Bronwyn E, Vutskits, Laszlo, Scheffer, Ingrid E, Petrou, Steven, Blaesse, Peter, Dibbens, Leanne M, Berkovic, Samuel F, Kaila, Kai
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01-06-2014; Nature Publishing Group UK; BlackWell Publishing Ltd
• Subjects: Amino Acid Sequence; Animals; Australia; Blotting, Western; Chlorides - metabolism; Convulsions & seizures; dendritic spines; Dendritic Spines - genetics; Dendritic Spines - pathology; EMBO24; EMBO27; febrile seizures; Genetic diversity; Genetic Predisposition to Disease - genetics; genic intolerance; Humans; K Cl- Cotransporters; KCC2; Mice; Mice, Inbred ICR; Microscopy, Fluorescence; Models, Molecular; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; Neurons; Neurons - metabolism; Pedigree; Protein Conformation; Proteins; Rats; Rats, Wistar; Scientific Report; Scientific Reports; Seizures, Febrile - genetics; Spine; Statistics, Nonparametric; Symporters - genetics; Symporters - metabolism; Australia; genic intolerance; mutation; KCC2; dendritic spines; febrile seizures
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1002/embr.201438749

Genetic variation in
SLC12A5
which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of
SLC12A5
revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl
−
extrusion and has a compromised ability to induce dendritic spines
in vivo
and
in vitro
. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a
bona fide
susceptibility variant for febrile seizures.
Synopsis
A missense mutation of the K‐Cl co‐transporter KCC2, identified in patients with febrile seizures, leads to defects in neuronal Cl
−
extrusion and dendritic spine formation
in vivo
and in cultured cells.
A rare
SLC12A5
variant with an arginine‐to‐histidine substitution at position 952 in the KCC2b isoform is identified in an Australian family with early childhood onset of febrile seizures.
Expression of the KCC2‐R952H variant leads to reduced Cl
−
extrusion, cortical dendritic spine formation and surface expression of the KCC2b protein.
The significant functional deficits taken together with the low genetic tolerance of
SLC12A5
are consistent with a role for KCC2‐R952H as a susceptibility gene in febrile seizures.
Graphical Abstract
A missense mutation of the K‐Cl co‐transporter KCC2, identified in patients with febrile seizures, leads to defects in neuronal Cl
−
extrusion and dendritic spine formation
in vivo
and in cultured cells.