A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity

Abstract

Although genetic factors are considered a main etiology of epilepsy, the causes of genetic epilepsy in the majority of epilepsy patients remain unknown. Kinesin family member 1A (KIF1A), a neuron-specific motor protein that moves along with microtubules, is responsible for the transport of membranous organelles and synaptic vesicles. Variants of <i>KIF1A</i> have recently been associated with hereditary spastic paraplegia (HSP), hereditary sensory and autonomic neuropathy type 2 (HSANII), and intellectual disability. However, mutations in <i>KIF1A</i> have not been detected in patients with epilepsy. In our study, we conducted customized sequencing of epilepsy-related genes of a family with six patients with generalized epilepsy over three generations and identified a rare heterozygous mutation (c.1190C > A, p. Ala397Asp) in <i>KIF1A</i>. Whole-cell recordings from primary cultured neurons revealed that the mutant <i>KIF1A</i> increases the excitatory synaptic transmission but not the intrinsic excitability of neurons, and phenotype testing in zebrafish showed that this rare mutation results in epileptic seizure-like activity. These results provide new evidence demonstrating that <i>KIF1A</i> dysfunction is involved in epileptogenesis.