Pathogenic potential of human SLC12A5 variants causing KCC2 dysfunction.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• SLC12A5 encodes the potassium-chloride cotransporter 2 (KCC2), essential for neuronal inhibition via GABA and glycine.
• KCC2 dysfunction disrupts the excitation-inhibition balance, potentially causing neurological and psychiatric disorders.
• While KCC2 function is known to be regulated by posttranslational modifications, its role in human disease remained largely undescribed until recently.

Purpose of the Study:

• To investigate the pathogenic potential of SLC12A5 variants in human diseases.
• To explore the link between KCC2 dysfunction and neurological disorders, particularly epilepsy.

Main Methods:

• Gene-targeted sequencing of SLC12A5, focusing on coding exons.
• Whole exome sequencing in patients with epilepsy.
• Functional assessment of identified KCC2 variants, including chloride extrusion capacity.

Main Results:

• The first reports of SLC12A5 variants associated with seizure disorders emerged approximately four years ago.
• Causative mutations in SLC12A5 have been identified in epilepsy patients through whole exome sequencing.
• These identified KCC2 variants exhibit impaired chloride extruding functions.

Conclusions:

• Loss-of-function variants in human SLC12A5 are confirmed to have pathogenic potential.
• KCC2 dysfunction, driven by SLC12A5 variants, plays a significant role in the pathogenesis of epilepsy and potentially other central nervous system disorders.