WNK3 Gene – Structure, Function, Mutations, and Clinical Significance

WNK3 (with-no-lysine [K] kinase 3) is a member of the WNK family of serine/threonine kinases, characterized by the atypical placement of the catalytic lysine residue. WNK3 regulates ion homeostasis by modulating the activity of cation-chloride cotransporters (e.g., NKCC1, NKCC2, KCC1–4) through phosphorylation. It is expressed in multiple tissues, including brain, kidney, and heart, and plays roles in cell volume regulation, neuronal excitability, and blood pressure control. Mutations and altered expression of WNK3 have been linked to X-linked intellectual disability, epilepsy, and various cancers.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• WNK regulation of ion transport (Reactome: R-HSA-2672351)

• SLC12A cotransporters (KEGG: hsa04964)

• PI3K-Akt signaling pathway (KEGG: hsa04151)

WNK3 is a 1,744-amino-acid serine/threonine kinase with a unique catalytic domain lacking the canonical lysine in subdomain II. It contains an N-terminal kinase domain, an autoinhibitory domain, and multiple coiled-coil regions. WNK3 phosphorylates and regulates SPAK/OSR1 kinases, which in turn modulate NKCC and KCC cotransporters. The protein is predominantly cytoplasmic but can translocate to the plasma membrane upon osmotic stress. Structural studies reveal that the kinase domain adopts a typical bilobal fold, with the active site stabilized by interactions with the atypical lysine (Lys-166).