SLC12A6 Gene - KCC3 Cotransporter: Function, Mutations & Disease

SLC12A6 (Solute Carrier Family 12 Member 6) encodes the potassium-chloride cotransporter KCC3, a member of the cation-chloride cotransporter (CCC) family. KCC3 mediates electroneutral K-Cl cotransport across the plasma membrane, playing a critical role in cell volume regulation, ion homeostasis, and neuronal development. Loss-of-function mutations in SLC12A6 cause Andermann syndrome (ACCPN), a severe hereditary motor and sensory neuropathy with agenesis of the corpus callosum. The gene is also implicated in cancer cell proliferation and migration.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Ion transport by P-type ATPases (Reactome R-HSA-936837)

• Cation-coupled chloride cotransporters (Reactome R-HSA-426117)

• Cell volume regulation (WikiPathways WP4530)

The KCC3 protein (UniProt Q9UHW9) is a 1150-amino acid multi-pass membrane protein with 12 transmembrane domains. It functions as a K-Cl cotransporter, extruding KCl from cells to regulate cell volume and chloride homeostasis. KCC3 is activated by cell swelling and dephosphorylation. Two major isoforms (KCC3a and KCC3b) differ in their N-terminal sequences and tissue distribution. Mutations that disrupt transport activity lead to axonal degeneration and the clinical features of Andermann syndrome.