Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families

摘要: Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a subtype, established as genetic influence for certain pain syndromes. In this study, we performed study six unrelated multigenerational Japanese families episodic syndrome. Affected participants (n = 23) were characterized by infantile recurrent episodes spontaneous mitigation around adolescence. This unique phenotype was inherited an autosomal-dominant mode. Linkage analysis two 12 affected and nine unaffected members, single locus identified on 3p22 (LOD score 4.32). Exome 14) members these additional family. Two missense variants identified: R222H R222S SCN11A. Next, generated knock-in mouse model harboring one of the (R222S). Behavioral tests (Hargreaves test cold plate test) using wild-type C57BL/6 (WT) mice, young (8–9 weeks old; n 10–12 each group) mature (36–38 5–6 group), showed that mice significantly (p < 0.05) more hypersensitive to hot stimuli than WT mice. Electrophysiological studies dorsal root ganglion neurons from 8–9-week-old no significant difference resting membrane potential, but input impedance firing frequency evoked action potentials increased compared However, there among Nav1.9 (WT, R222S, R222H)-overexpressing ND7/23 cell lines. These results suggest our novel mutation is gain-of-function causes familial pain. The developed here will be useful drug screening syndrome associated SCN11A mutations.