Pathogenic potential of human SLC12A5 variants causing KCC2 dysfunction.

SLC12A5 encodes K+-Cl- cotransporter 2 (KCC2), which is the main Cl- extruder of neurons, and renders the proper inhibitory function of the neurotransmitters γ-aminobutyric acid (GABA) and glycine. Thus, any variant in SLC12A5, if it causes dysfunction of KCC2, could be pathogenic for neurological and psychiatric disorders by disrupting inhibition and causing collapse of the excitation-inhibition balance. KCC2 functions are regulated by posttranslational modifications, such as phosphorylation and glycosylation. Therefore, if a variant hampers any of these regulators, Cl- transporting activity of KCC2 may be disturbed. As such, it is natural to think KCC2 variants are implicated in multiple central and peripheral nervous system disorders. Indeed, a number of investigations have been undertaken to determine the impact of identified variants on KCC2 function. However, no variants of KCC2 have been described in human disease until recently. Thanks to the next generation sequencer and decrements in the cost for sequencing, the first reports of variants in KCC2 as risk factors for seizure disorders were made only 4 years ago, by means of gene-targeted sequencing of SLC12A5 (either all 26 coding exons or selected exons encoding the C-terminus). More recently, by means of whole exome sequencing, causative mutations have been found in patients with epilepsy. These variant KCC2 demonstrate impaired Cl- extruding functions. Thus, it is clear that the loss-of-function variants of human SLC12A5 have pathogenic potential.