Figure 1

Epilepsy mutations cluster at the S4, the pore, and the S6 domains of K_v7.2. (a) Pie charts showing the relative proportions of different types of epilepsy variants in human K_v7.2 (left) and of single amino acid K_v7.2 mutations that cause epilepsy with different clinical severity including “mild or BFNE”, “uncertain severity”, and “severe or epileptic encephalopathy (EE)” (right). All mutations identified up to December 31, 2017 are shown in Supplementary Table S1. (b) Single amino acid mutations except for 2 missense mutations in the primary start ATG codon (green markers) and silent mutations (purple markers) are mapped to K_v7.2 primary structure (NP_742105.1). The MHF statistical algorithm identified S4, the pore loop, and S6 as hotspots for all pathogenic epilepsy mutations (brackets, ***p < 0.005, Supplementary Table S2). (c) The MHF algorithm revealed S4, the pore loop, and S6 as hotspots for “severe or EE” mutations (brackets, **p < 0.01, ***p < 0.005, Supplementary Table S3). (d) The S1-S6 domains of tetrameric human K_v7.2 were modeled based on the cryoEM structure of Xenopus K_v7.1 (Protein Data Bank: 5VMS)²⁸. At left, two opposing subunits are viewed from the plane of the plasma membrane. At right, the model is viewed from the extracellular space, with two opposing subunits shown as ribbons and their neighbors shown as transparent surfaces. Sites of pathogenic mutations are highlighted with colored spheres on the C-alpha atoms of one subunit: mild or BFNE (blue), uncertain severity (purple), severe or EE (red). Where more than one mutation occurs at a single position, the residue is colored by the most severe phenotype. (e) Location of amino acids mutated in mild or BFNE (blue), uncertain severity (purple), or severe or EE (red) in S4, the pore loop and S6 of K_v7.2.