The FGF14F145S 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 ( alpha) 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 alpha subunit expression at the axon initial segment, attenuates Nav 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 Na-v channel alpha subunits. Rather, FGF14(F145S) associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na-v alpha subunits, suggesting that the mutant FGF14(F145S) protein acts as a dominant negative, interfering with the interaction between wild- type FGF14 and Nav channel alpha subunits and altering neuronal excitability.