Role of TRPM4 ion channel in pediatric arrhythmic syndromes

Figure 1 Overall architecture of the hTRPM4 subunit. A: A schematic representation of the major structural components in hTRPM4; the N-terminus has four melastatin regions and Pre-S1 region; the transmembrane domain contains six helices (S1-S6); helices S5, S6 and P-loop form pore module; the C-terminus contains transient receptor potential and C-terminal domain helices; alpha-helices are represented by cylinders and beta-strands are indicated by arrows; variants are numbered: 1-E7K; 2-R164W; 3-D198G; 4-A432T; 5-V441M; 6-R499W; 7-G582S; 8-T677I; 9-P779R; 10-R819C; 11-G844D; 12-T873I; 13-K914X; 14-V921I; 15-R964S; 16-L1075P; 17-K1140X; B: 3D model of the hTRPM4 subunit (PDB ID: 5WP6). MHR1-4: Four melastatin regions; TM: Transmembrane; TRP: Transient receptor potential; CTD: C-terminal domain.

Figure 2 Electrocardiography during sinus rhythm with heart rate 85-154 bpm.

Figure 3 The duration of rhythm pauses ranged from 1800 milliseconds to 2976 milliseconds. А: Pectoral leads; B: Standard leads.

Figure 4 TRPM4 cryoEM structure. A: Extracellular view of the TRPM4 cryoEM structure (PDB ID: 5wp6). Four identical subunits are differently colored to highlight intersubunit contacts of the four R964 residues, which stabilize the folding of P-loops that harbor the channel selectivity-filter; arginine R964 in P-loop helix P1 and glycine G976 in the selectivity filter are shown by spherical atoms; B: Close-up views of 3D-aligned AlphaFold 3 (AF3) models of the wildtype channel TRPM4 (green) and R964S mutant channel (brown); mutation R964S eliminates the salt bridge that stabilizes an intersubunit contact between helix P1 and a linker connecting the selectivity filter and helix S6; C: Close-up view of the selectivity filter region in the AF3 models; elimination of the intersubunit contact (B) cases a noticeable widening of the selectivity-filter region that likely affects the ion selectivity of the channel.

Figure 5 Echocardiography and Electrocardiography findings: A and B: At 3 months of age: Left ventricular dilation with spherical configuration and diffuse repolarization abnormalities, including T-wave inversion on electrocardiography (ECG); C and D: At 2 years of age: Normalization of left ventricular size (LVEDD 24. 5 mm; Z-score +1.96) and resolution of T-wave inversion with normalized repolarization patterns on ECG.