Figure 1.

Disease mutations in the C-terminus of Na_v1.5. (a) Schematic depiction of the structural entities of the channel. (b) Disease-associated mutations plotted on Na_v1.5 C-terminal domain (red, light brown) interacting with Mg²⁺-loaded CaM (grey; PDB ID 4OVN). This region is immediately downstream of the last transmembrane segment and contains the EF-hand domain (beige), an additional helix (orange), and an IQ motif (red) that binds CaM. The disease-causing mutations are linked to LQT3 (black), BrS (blue), or both (brown). (c) Thermal denaturation curves for wild type and disease mutant EF-hand domain constructs using a Thermofluor assay. The displayed curves are an average of at least three measurements. The melting temperatures, standard errors, and number of repeats are shown in Table S1. R1860Gfs*12 is a frameshift mutation, which leads to a premature stop of translation after 11 amino acids of non-WT sequence.