Familial episodic limb pain in kindreds with novel Nav1.9 mutations

Risako Kabata, Hiroko Okuda, Atsuko Noguchi, Daiki Kondo, Michimasa Fujiwara, Kenichiro Hata, Yoshifumi Kato, Ken Ishikawa, Manabu Tanaka, Yuji Sekine, Nozomi Hishikawa, Tomoyuki Mizukami, Junichi Ito, Manami Akasaka, Ken Sakurai, Takeshi Yoshida, Hironori Minoura, Takashi Hayashi, Kohei Inoshita, Misayo MatsuyamaNoriko Kinjo, Yang Cao, Sumiko Inoue, Hatasu Kobayashi, Kouji H. Harada, Shohab Youssefian, Tsutomu Takahashi, Akio Koizumi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p. V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p. F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p. F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.

Original languageEnglish
Article numbere0208516
JournalPloS one
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 1 2018

Fingerprint

Polytetrafluoroethylene
limbs (animal)
pain
Extremities
mutation
Pain
Mutation
mice
action potentials
Neurons
Action Potentials
adolescence
neurons
Deterioration
Membranes
membrane potential
genetic techniques and protocols
Spinal Ganglia
animal models
deterioration

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Kabata, R., Okuda, H., Noguchi, A., Kondo, D., Fujiwara, M., Hata, K., ... Koizumi, A. (2018). Familial episodic limb pain in kindreds with novel Nav1.9 mutations. PloS one, 13(12), [e0208516]. https://doi.org/10.1371/journal.pone.0208516

Familial episodic limb pain in kindreds with novel Nav1.9 mutations. / Kabata, Risako; Okuda, Hiroko; Noguchi, Atsuko; Kondo, Daiki; Fujiwara, Michimasa; Hata, Kenichiro; Kato, Yoshifumi; Ishikawa, Ken; Tanaka, Manabu; Sekine, Yuji; Hishikawa, Nozomi; Mizukami, Tomoyuki; Ito, Junichi; Akasaka, Manami; Sakurai, Ken; Yoshida, Takeshi; Minoura, Hironori; Hayashi, Takashi; Inoshita, Kohei; Matsuyama, Misayo; Kinjo, Noriko; Cao, Yang; Inoue, Sumiko; Kobayashi, Hatasu; Harada, Kouji H.; Youssefian, Shohab; Takahashi, Tsutomu; Koizumi, Akio.

In: PloS one, Vol. 13, No. 12, e0208516, 01.12.2018.

Research output: Contribution to journalArticle

Kabata, R, Okuda, H, Noguchi, A, Kondo, D, Fujiwara, M, Hata, K, Kato, Y, Ishikawa, K, Tanaka, M, Sekine, Y, Hishikawa, N, Mizukami, T, Ito, J, Akasaka, M, Sakurai, K, Yoshida, T, Minoura, H, Hayashi, T, Inoshita, K, Matsuyama, M, Kinjo, N, Cao, Y, Inoue, S, Kobayashi, H, Harada, KH, Youssefian, S, Takahashi, T & Koizumi, A 2018, 'Familial episodic limb pain in kindreds with novel Nav1.9 mutations', PloS one, vol. 13, no. 12, e0208516. https://doi.org/10.1371/journal.pone.0208516
Kabata R, Okuda H, Noguchi A, Kondo D, Fujiwara M, Hata K et al. Familial episodic limb pain in kindreds with novel Nav1.9 mutations. PloS one. 2018 Dec 1;13(12). e0208516. https://doi.org/10.1371/journal.pone.0208516
Kabata, Risako ; Okuda, Hiroko ; Noguchi, Atsuko ; Kondo, Daiki ; Fujiwara, Michimasa ; Hata, Kenichiro ; Kato, Yoshifumi ; Ishikawa, Ken ; Tanaka, Manabu ; Sekine, Yuji ; Hishikawa, Nozomi ; Mizukami, Tomoyuki ; Ito, Junichi ; Akasaka, Manami ; Sakurai, Ken ; Yoshida, Takeshi ; Minoura, Hironori ; Hayashi, Takashi ; Inoshita, Kohei ; Matsuyama, Misayo ; Kinjo, Noriko ; Cao, Yang ; Inoue, Sumiko ; Kobayashi, Hatasu ; Harada, Kouji H. ; Youssefian, Shohab ; Takahashi, Tsutomu ; Koizumi, Akio. / Familial episodic limb pain in kindreds with novel Nav1.9 mutations. In: PloS one. 2018 ; Vol. 13, No. 12.
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abstract = "We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p. V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p. F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p. F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.",
author = "Risako Kabata and Hiroko Okuda and Atsuko Noguchi and Daiki Kondo and Michimasa Fujiwara and Kenichiro Hata and Yoshifumi Kato and Ken Ishikawa and Manabu Tanaka and Yuji Sekine and Nozomi Hishikawa and Tomoyuki Mizukami and Junichi Ito and Manami Akasaka and Ken Sakurai and Takeshi Yoshida and Hironori Minoura and Takashi Hayashi and Kohei Inoshita and Misayo Matsuyama and Noriko Kinjo and Yang Cao and Sumiko Inoue and Hatasu Kobayashi and Harada, {Kouji H.} and Shohab Youssefian and Tsutomu Takahashi and Akio Koizumi",
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AU - Kabata, Risako

AU - Okuda, Hiroko

AU - Noguchi, Atsuko

AU - Kondo, Daiki

AU - Fujiwara, Michimasa

AU - Hata, Kenichiro

AU - Kato, Yoshifumi

AU - Ishikawa, Ken

AU - Tanaka, Manabu

AU - Sekine, Yuji

AU - Hishikawa, Nozomi

AU - Mizukami, Tomoyuki

AU - Ito, Junichi

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AU - Yoshida, Takeshi

AU - Minoura, Hironori

AU - Hayashi, Takashi

AU - Inoshita, Kohei

AU - Matsuyama, Misayo

AU - Kinjo, Noriko

AU - Cao, Yang

AU - Inoue, Sumiko

AU - Kobayashi, Hatasu

AU - Harada, Kouji H.

AU - Youssefian, Shohab

AU - Takahashi, Tsutomu

AU - Koizumi, Akio

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AB - We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p. V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p. F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p. F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.

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