Abstract The etiology of epilepsy remains undefined in two-thirds of patients. Here, we identified a de novo mutation of ATP1A2 (c.2426 T&gt;G, p.Leu809Arg), which encodes the α2 subunit of Na + /K + -ATPase, from a family with idiopathic epilepsy. This mutation caused seizures in the study patients. We generated the point mutation mouse model Atp1a2 L809R , which recapitulated the epilepsy observed in the study patients. In Atp1a2 L809R/WT mice, convulsions were observed and cognitive and memory function was impaired. This mutation affected the potassium binding function of the protein, disabling its ion transport ability, thereby increasing the frequency of nerve impulses. Our work revealed that ATP1A2 L809R mutations cause a predisposition to epilepsy. Moreover, we first provide a point mutation mouse model for epilepsy research and drug screening.

Recurrent de novo single point mutation on the gene encoding Na+/K+ pump results in epilepsy