The FGF14^F145S mutation disrupts the interaction of FGF14 with voltage-gated Na⁺ channels and impairs neuronal excitability

Fibroblast growth factor 14 (FGF14) belongs to the intracellular FGF homologous factor subfamily of FGF proteins (iFGFs) that are not secreted and do not activate tyrosine kinase receptors. The iFGFs, however, have been shown to interact with the pore-forming (α) subunits of voltage-gated Na ⁺ (Na_v) channels. The neurological phenotypes seen in Fgf14^-/- mice and the identification of an FGF14 missense mutation (FGF14^F145S) in a Dutch family presenting with cognitive impairment and spinocerebellar ataxia suggest links between FGF14 and neuronal functioning. Here, we demonstrate that the expression of FGF14^F145S reduces Na_v α subunit expression at the axon initial segment, attenuates Na_v channel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14^F145S does not interact directly with Nav channel α subunits. Rather, FGF14^F145S associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na_v α subunits, suggesting that the mutant FGF14^F145S protein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Na_v channel α subunits and altering neuronal excitability.