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Recurrent de novo single point variant on the gene encoding Na/K pump results in epilepsy. | LitMetric
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 α2 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, which recapitulated the epilepsy observed in the study patients. In Atp1a2 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 mice. Our work revealed that ATP1A2 variants cause a predisposition to epilepsy. Moreover, we provide a point variant mouse model for epilepsy research and drug screening.
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