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+(Nav) channels. The neurological phenotypes seen inFgf14−/−mice and the identification of anFGF14missense mutation (FGF14F145S) 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 FGF14F145Sreduces Navα subunit expression at the axon initial segment, attenuates Navchannel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14F145Sdoes not interact directly with Navchannel α subunits. Rather, FGF14F145Sassociates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Navα subunits, suggesting that the mutant FGF14F145Sprotein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Navchannel α subunits and altering neuronal excitability.