Figure 1.

Schema of the pore-forming α subunit of Na_v1.4 and location of A204E. (A) The pore-forming α subunit of hNa_v1.4 is composed of 1.836 amino acid residues forming 4 homologous domains (DI-DIV). Each domain is composed of 6 transmembrane segments (S1–S6). The S1–S4 segments of each domain form the voltage-sensor domain, with the positively-charged S4 segments acting as voltage-sensors while the S5 and S6 segments form the selective α pore. More than 70 mutations have been described in human Na_v1.4. Only the ones located in DIS3 or phenotypically-related to A204E are listed on the schema: p.M203K located in DIS3 and associated to a congenital myopathy phenotype; the hypoPP missense mutations substituting positively-charged (+) residues in S4 segments; p.R1451L resulting in a PP phenotype combining hyper- and hypo-PP. The p.R1129Q and p.R1451L are associated with two distinct phenotypes: hypoPP or normoPP (R1129Q), and paramyotonia congenita with hyperPP or PP combining hyper- and hypo-PP signs (R1451L). Hyper PP = hyperkalaemic periodic paralysis; hypoPP = hypokalaemic periodic paralysis; PMC = paramyotonia congenita; NormoPP = normokalaemic PP; CM = congenital myopathy. (B) Model of voltage-sensor domain I based on Na_vAb crystal structure⁴⁰ showing the position of the Ala204 residue on the extracellular side of S3. (C) Alignment of the hNa_v1.4 amino acid sequence around the A204 residue with eukaryotic EeNav1.4 (electric eel) and Na_VPaS (putative Na_v channel from the American cockroach) channels whose cryo-electron microscopy structure was determined with a high-level resolution. The A204 residue is not conserved in these orthologs except in EeNav1.4b.