CAMSAP3 loss of function models suggest causative role in generalized genetic epilepsy

Advancements in next-generation sequencing have led to the discovery of hundreds of human epilepsy gene associations. Newly associated genes require functional validation to establish causation and to inform patient treatment in the clinic. A recent exome sequencing trio analysis identified predicted protein-altering variants in two patients with generalized epilepsy in the gene CAMSAP3 . CAMSAP3 regulates non-centrosomal microtubule dynamics and the acetylation necessary for normal axonal differentiation and migration. We show that overexpression of patient variants leads to protein degradation and dysregulation of microtubule acetylation in cultured HEK cells. Camsap3 knockout zebrafish also exhibit increased axonal microtubule acetylation, as well as epileptic features such as seizure-like swimming behaviors, aberrant inhibitory interneuron development, and epileptiform via electrophysiology. Together, these data suggest that CAMSAP3 plays an important role in genetic generalized epilepsy.

Loss-of-function CAMSAP3 variants in individuals with genetic generalized epilepsy alter tubulin dynamics in HEK cells. Camsap3 loss-of-function zebrafish show dysregulation of acetylated tubulin in tectal axon projections. Mutant fish exhibit hyperexcitable swimming behavior, loss of inhibitory interneurons and epileptiform via electrophysiology.