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

The etiology of epilepsy remains undefined in two-thirds of patients. Here, we identified a de novo variant of ATP1A2 (c.2426 T > G, p.Leu809Arg), which encodes the alpha 2 subunit of Na+/K+-ATPase' from a family with idiopathic epilepsy. This variant caused epilepsy with hemiplegic migraine in the study patients. We generated the point variant 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 variant affected the potassium binding function of the protein, disabling its ion transport ability, thereby increasing the frequency of nerve impulses. Valproate (VPA) and Carbamazepine (CBZ) have limited therapeutic efficacy in ameliorating the epileptic syndromes of Atp1a2(L809R/WT) mice. Our work revealed that ATP1A2(L809R) variants cause a predisposition to epilepsy. Moreover, we provide a point variant mouse model for epilepsy research and drug screening.

Automated summary

The etiology of epilepsy remains undefined in two-thirds of patients. This study identified a de novo variant of ATP1A2 (c.2426 T > G, p.Leu809Arg) that is associated with idiopathic epilepsy and hemiplegic migraine. The variant affects the function of the Na+/K+-ATPase and leads to increased frequency of nerve impulses. A point variant mouse model was generated to study epilepsy and drug screening.