Interestingly, substitution of the first methionine (Ma) in this linker (Figure 1C) with a positively charged residue (M1627K) in Nav1.7 causes PEPD ([19] and this study), while substitution with a hydrophobic residue isoleucine (M1476I) in Nav1.4 causes cold-induced myotonia [42]. The gene discussed is SCN9A; the disease is paroxysmal extreme pain disorder.