Identification of a novel pain gene and its application to prevention and drug development

• Project/Area Number: 26670330
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hygiene and public health
• Research Institution: Kyoto University
• Principal Investigator: KOIZUMI Akio 京都大学, 医学研究科, 教授 (50124574)
• Co-Investigator(Kenkyū-buntansha): 高橋 勉 秋田大学, 医学(系)研究科(研究院), 教授 (20270845) ; 原田 浩二 京都大学, 医学研究科, 准教授 (80452340) ; 人見 敏明 聖マリアンナ医科大学, 医学部, 准教授 (90405275) ; 小林 果 京都大学, 医学研究科, 特定講師 (70542091)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 分子疫学 / 痛みの遺伝学 / 創薬

Outline of Final Research Achievements

Genetic investigation of 3 pedigrees of paroxysmal limb intermittent pain (PLIP), which had 28 members, revealed Nav1.9 R222H or R222S mutation as a causative polymorphism. These polymorphisms were not found in a 150 Japanese controls. Further nation-wide investigation found 24 new families suspected of PLIP. Genetic investigation revealed R222H in 5 families and 3 novel mutations in 3 families. In those families, limb pain was induced by low atmospheric pressure and cold weather in affected members. Their symptoms were ameliorated by growth and aging. Symptoms of GI tract were not detected. Knock-in mice which harbor R222S was proven to have elevated sensitivity to the pain by behavioral test batteries and by electrophysiological examinations. This study demonstrated that Nav1.9 causes PLIP and will pave a way to develop a prevention strategy and new therapeutic approach.

Research Products

• [Journal Article] Infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome in Japanese families (2016)
  • Author(s): Hiroko Okuda, Atsuko Noguchi, Hatasu Kobayashi, Daiki Kondo, Kouji H.Harada, Shohab Youssefian, Hirotomo Shioi, Risako kabata, Yuki Domon,Kazufumi Kubota, Yutaka Kitano, Yasunori Takayama, Toshiaki Hitomi,Kousaku Ohno, Yoshiaki Saito, Takeshi Asano, Makoto Tominaga, Tsutomu Takahashi, and Akio Koizumi.
  • Journal Title: PLOS ONE Volume: 11 Issue: 5 Pages: e0154827-e0154827
  • DOI: 10.1371/journal.pone.0154827
  • NAID: 120005946996
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The importance of molecular diagnosis in the accurate diagnosis of systemic carnitine deficiency (2015)
  • Author(s): Hitomi T, Matsuura N, Shigematsu Y, Okano Y, Shinozaki E, Kawai M, Kobayashi H, Harada KH, Koizumi A.
  • Journal Title: Journal of Genetics Volume: 94（1） Issue: 1 Pages: 147-150
  • DOI: 10.1007/s12041-015-0486-0
  • Peer Reviewed
• [Journal Article] Early onset of moyamoya syndrome in a Down syndrome patient with the genetic variant RNF213 p.R4810K (2015)
  • Author(s): Pin Fee Chong, Reina Ogata, Hatasu Kobayashi, Akio Koizumi, Ryutaro Kira
  • Journal Title: Brain Dev. Available Volume: Available online Issue: 8 Pages: 822-4
  • DOI: 10.1016/j.braindev.2014.12.006
  • Peer Reviewed
• [Journal Article] Genetic Study of Intracranial Aneurysms (2015)
  • Author(s): Yan JX, Hitomi T, Takenaka K, Kato M, Kobayashi H, Okuda H, Harada KH, Koizumi A.
  • Journal Title: Stroke Volume: 46(3) Issue: 3 Pages: 620-626
  • DOI: 10.1161/strokeaha.114.007286
  • Peer Reviewed
• [Journal Article] An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka (2014)
  • Author(s): Nanayakkara, S., Senevirathna, S., Abeysekera, T., Chandrajith, R., Ratnatunga, N., Gunarathne, E., Yan, J., Hitomi, T., Muso, E., Komiya, T., Harada, K., Liu, W., Kobayashi, H., Okuda, H., Sawatari, H., Matsuda, F., Yamada, R., Watanabe, T., Miyataka, H., Himeno, S., Koizumi, A.
  • Journal Title: Journal of Occupational Health Volume: 56 Issue: 1 Pages: 28-38
  • DOI: 10.1539/joh.13-0172-OA
  • NAID: 130004848049
  • ISSN: 1341-9145, 1348-9585
  • Peer Reviewed
• [Presentation] Nav1.9遺伝子変異が同定された小児四肢疼痛発作症の日本人家系 (2016)
  • Author(s): 野口篤子、近藤大喜、奥田裕子、小林果、斎藤義朗、大野耕策、浅野健、原田浩二、小泉昭夫、高橋勉
  • Organizer: 第26回 日本小児リウマチ学会総会・学術集会
  • Place of Presentation: 千葉市民会館
  • Year and Date: 2016-10-21
• [Presentation] 原因不明の家族性慢性疼痛症の責任遺伝子としてSCN11A遺伝子を同定した (2016)
  • Author(s): 小林果、奥田裕子、人見敏明、塩井大智、原田浩二、小泉昭夫
  • Organizer: 第86回 日本衛生学会総会
  • Place of Presentation: 旭川市民文化会館
  • Year and Date: 2016-05-11
• [Presentation] 慢性疼痛症モデルマウスの作成と疼痛行動解析 (2016)
  • Author(s): 塩井大智、崔廷米、奥田裕子、小林果、原田浩二、小泉昭夫
  • Organizer: 第86回 日本衛生学会総会
  • Place of Presentation: 旭川市民文化会館
  • Year and Date: 2016-05-11
• [Presentation] 周期性四肢関節症の疼痛マウスモデルの電気生理学的解析 (2016)
  • Author(s): 奥田裕子、小林果、原田浩二、小泉昭夫
  • Organizer: 第86回 日本衛生学会総会
  • Place of Presentation: 旭川市民文化会館
  • Year and Date: 2016-05-11
• [Remarks] 京都大学大学院医学研究科環境衛生学分野HP
  • URL: http://hes.med.kyoto-u.ac.jp/
• [Remarks] 京都大学大学院医学研究科環境衛生学分野ＨＰ
  • URL: http://hes.med.kyoto-u.ac.jp/
• [Patent(Industrial Property Rights)] 疼痛遺伝子及びその用途 (2014)
  • Inventor(s): 小泉昭夫、小林果、原田浩二、人見敏明、土生敏行、高橋勉、他2名
  • Industrial Property Rights Holder: 国立大学法人京都大学、国立大学法人秋田大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-238250
  • Filing Date: 2014-11-25