case_images: PMC10570449_01
case_images: (A) The pedigree chart. The arrow indicates the proband with HypoKPP (Wt:wild type allele). (B) Sanger sequencing chromatograms (revers variant) shows wild type allele (a) and c.2699G > T mutation (b).
case_images: fneur-14-1267426-g001.jpg
case_images: PMC10570449_01_fneur-14-1267426-g001.jpg
case_images: fig1
case_images: There was no family history on similar symptoms or any neurological disorders (parents, two sibs are clinically unaffected) (Figure 1A). The substitution was further confirmed by Sanger sequencing (Figure 1B).
case_images: Architecture of the hetero-tetrameric voltage-gated human calcium channel CaV1.1. (A) Schematic representation of four domains (I-IV) of the alpha1S subunit. S1-S6 transmembrane helices and four positive charges of S4 helix are shown in each domain. (B) Alignment of S4 segments of domains I-IV of CaV1.1. Positively charged Arg residues (R1-R4) are highlighted in color. The Arg900Met mutation is highlighted in the IIIS4M (mutated) segment. (C) Structural model of the alpha1S subunit of CaV1.1. View from the extracellular space is presented. The color coding of domains corresponds to (A). Transmembrane helices S1-S4 forming a voltage sensor (VS) are denoted in domain III. Yellow sphere in the center represents Ca2+ ion in the selective filter of the channel. (D,E) Structural models of VS-III in the activated state in the native and mutated forms, respectively. Residues R1-R4 of the S4 helix are shown, as well as residues E819, D836, E846, and F843 of the S2 helix interacting with them. The side chain of R900 is highlighted in yellow (D). Ionic contacts formed by R900 with residues E819 and D836 are shown as red dashed lines.
case_images: fneur-14-1267426-g002.jpg
case_images: PMC10570449_01_fneur-14-1267426-g002.jpg
case_images: fig2
case_images: A schematic representation and structural model of the alpha1S subunit of CaV1.1 are shown in Figures 2A,C. Aligned sequences of S4 segments are shown in Figure 2B. The alpha1 subunit of CaV includes four domains I-IV, each of which contains six transmembrane helices S1-S6 (Figure 2A). The S1-S4 helices form the VSD of the channel (Figure 2C). Each S4 helix contains positively charged Arg and Lys residues (Figure 2B). III (Arg897, Arg900, Arg903, and Arg906) alternately form ion pairs with countercharges of the S2 helix (Asp836 and Glu846) when the helix moves in an electric field. In our CaV1.1 model, VS is in an activated state, and Arg900 (R2) forms salt bridges with Asp836 and Glu819 residues (Figure 2D). MC minimization showed that these contacts are lost when positively charged Arg900 is replaced by nonpolar Met (Figure 2E).