title: Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.
abstract: Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuda
authors.affiliation: Department of Pediatrics, Akita University School of Medicine, Akita, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Noguchi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Akita University School of Medicine, Akita, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Kondo
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.affiliation: Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shohab
authors.initials: S
authors.lastname: Youssefian
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Shioi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Kabata
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Domon
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kitano
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Takayama
authors.affiliation: Department of Preventive Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.affiliation: Department of Pediatrics, Sanin Rosai Hospital, Tottori, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Tottori, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Pediatrics, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Asano
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
authors.affiliation: Department of Pediatrics, Akita University School of Medicine, Akita, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000200:Action Potentials; D019943:Amino Acid Substitution; D000818:Animals; D044466:Asian People; D002460:Cell Line; D005190:Family; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008040:Genetic Linkage; D056426:Genetic Loci; D006801:Humans; D007564:Japan; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010375:Pedigree; D013577:Syndrome
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; C491886:SCN11A protein, human; C491885:Scn11a protein, mouse