Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy

• Published in: EMBO reports Vol. 15; no. 7; pp. 766 - 774
• Main Authors: Kahle, Kristopher T, Merner, Nancy D, Friedel, Perrine, Silayeva, Liliya, Liang, Bo, Khanna, Arjun, Shang, Yuze, Lachance-Touchette, Pamela, Bourassa, Cynthia, Levert, Annie, Dion, Patrick A, Walcott, Brian, Spiegelman, Dan, Dionne-Laporte, Alexandre, Hodgkinson, Alan, Awadalla, Philip, Nikbakht, Hamid, Majewski, Jacek, Cossette, Patrick, Deeb, Tarek Z, Moss, Stephen J, Medina, Igor, Rouleau, Guy A
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.07.2014; Nature Publishing Group UK; Springer Nature B.V; BlackWell Publishing Ltd
• Subjects: Action Potentials; Alleles; Animals; Case-Control Studies; cation-chloride cotransporters; Cell Line; Chlorides - metabolism; EMBO20; EMBO24; EMBO27; Epilepsy; Epilepsy, Generalized - genetics; Epilepsy, Generalized - metabolism; GABA; Gene Frequency; Genetic Variation; Genetics; Hippocampus - metabolism; Humans; K Cl- Cotransporters; KCC2; kinase; Models, Molecular; Mutation; Phosphorylation; Protein Conformation; Protein Interaction Domains and Motifs; Pyramidal Cells - metabolism; Quebec; Rats; Risk factors; Scientific Report; Scientific Reports; Symporters - chemistry; Symporters - genetics; Symporters - metabolism; Quebec; epilepsy; GABA; cation‐chloride cotransporters; kinase; KCC2
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201438840

The KCC2 cotransporter establishes the low neuronal Cl − levels required for GABA A and glycine (Gly) receptor‐mediated inhibition, and KCC2 deficiency in model organisms results in network hyperexcitability. However, no mutations in KCC2 have been documented in human disease. Here, we report two non‐synonymous functional variants in human KCC2, R952H and R1049C, exhibiting clear statistical association with idiopathic generalized epilepsy (IGE). These variants reside in conserved residues in the KCC2 cytoplasmic C‐terminus, exhibit significantly impaired Cl − ‐extrusion capacities resulting in less hyperpolarized Gly equilibrium potentials (E G ly ), and impair KCC2 stimulatory phosphorylation at serine 940, a key regulatory site. These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be a risk factor for the development of human IGE. Synopsis Two variants of the neuronal chloride cotransporter KCC2—R952H and R1049C—are found to be associated with human idiopathic generalized epilepsy and to impair transporter function and regulatory phosphorylation. Genetically encoded impairment of KCC2 function may therefore be a risk factor for human epilepsy. Two functional variants in KCC2, R952H and R1049C, are significantly associated with human idiopathic generalized epilepsy (IGE) Compared to WT KCC2, R952H and R1049C exhibit significantly impaired Cl − ‐extrusion capacities, result in less hyperpolarized glycine equilibrium potentials (EGly), and impair KCC2 serine 940 phosphorylation. Graphical Abstract Two variants of the neuronal chloride cotransporter KCC2—R952H and R1049C—are found to be associated with human idiopathic generalized epilepsy and to impair transporter function and regulatory phosphorylation. Genetically encoded impairment of KCC2 function may therefore be a risk factor for human epilepsy.