Development of a new method to predict disease-causing mechanisms of missense mutations

• Project/Area Number: 15K21487
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Life / Health / Medical informatics; Medical genome science
• Research Institution: Nagahama Institute of Bio-Science and Technology
• Principal Investigator: HIJIKATA Atsushi 長浜バイオ大学, バイオサイエンス学部, プロジェクト特任講師 (80415273)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ミスセンス変異 / 遺伝性疾患 / タンパク質立体構造 / データベース / ハプロ不全 / ドミナントネガティブ / 機能獲得変異 / 超分子複合体 / 優性阻害 / 機能獲得 / ヒト遺伝子疾患 / 疾患変異解析 / 構造バイオインフォマティクス

Outline of Final Research Achievements

Estimating molecular mechanisms of missense mutations on a particular disease is still challenging in the research field. In this study, I analyzed disease-causing missense mutations with its positions on protein structure, especially on macromolecular structures and found a clear relationship between the disease-causing mechanisms and the mutation residue positions on the 3D structures. According to the relationship, I developed a novel method to predict the disease-causing mechanisms caused by given missense mutations.

Research Products

• [Journal Article] Decoding disease-causing mechanisms of missense mutations from supramolecular structures (2017)
  • Author(s): Hijikata A, Tsuji T, Shionyu M, Shirai T
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8541-8541
  • DOI: 10.1038/s41598-017-08902-1
  • Peer Reviewed / Open Access
• [Journal Article] Structural and Functional Analysis of the C-Terminal Region of FliG, an Essential Motor Component of Vibrio Na + -Driven Flagella (2017)
  • Author(s): Miyanoiri Yohei、Hijikata Atsushi、Nishino Yuuki、Gohara Mizuki、Onoue Yasuhiro、Kojima Seiji、Kojima Chojiro、Shirai Tsuyoshi、Kainosho Masatsune、Homma Michio
  • Journal Title: Structure Volume: 25 Issue: 10 Pages: 1540-1548
  • DOI: 10.1016/j.str.2017.08.010
  • NAID: 120006375873
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular Mechanism and Structural Basis of Gain of Function of STAT1 Caused by Pathogenic R274Q Mutation (2017)
  • Author(s): Fujiki R, Hijikata A, Shirai T, Okada S, Kobayashi M, Ohara O
  • Journal Title: J Biol Chem. Volume: 292 Issue: 15 Pages: 6240-6254
  • DOI: 10.1074/jbc.m116.753848
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms of insulin resistance in 2 cases of primary insulin receptor defect-associated diseases. (2017)
  • Author(s): Tsuji-Hosokawa, A., Takasawa, K., Nomura, R., Miyakawa, Y., Numakura, C., Hijikata, A., Shirai, T., Ogawa, Y., Kashimada, K. & Morio, T.
  • Journal Title: Pediatr Diabetes Volume: Feb 9 Issue: 8 Pages: 917-924
  • DOI: 10.1111/pedi.12508
  • Peer Reviewed
• [Journal Article] The role of the Prod1 membrane anchor in newt limb regeneration (2017)
  • Author(s): Nomura, K., Tanimoto, Y., Hayashi, F., Harada, E., Shan, X.-Y., Shionyu, M., Hijikata, A., Shirai, T., Morigaki, K., Shimamoto, K.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 56 Issue: 1 Pages: 270-274
  • DOI: 10.1002/anie.201609703
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell-Based Phenotype Dissection. (2017)
  • Author(s): Kawasaki Y, Oda H, Ito J, Niwa A, Tanaka T, Hijikata A, Seki R, Nagahashi A, Osawa M, Asaka I, Watanabe A, Nishimata S, Shirai T, Kawashima H, Ohara O, Nakahata T, Nishikomori R, Heike T, Saito MK.
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 2 Pages: 447-459
  • DOI: 10.1002/art.39960
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel AVPR2 mutation causing partial nephrogenic diabetes insipidus in a Japanese family (2016)
  • Author(s): Yamashita S, Hata A, Usui T, Oda H, Hijikata A, Shirai T, Kaneko N, Hata D
  • Journal Title: J. Pediatr. Endocrinol. Metab. Volume: 5 Issue: 5 Pages: 591-596
  • DOI: 10.1515/jpem-2015-0323
  • Peer Reviewed
• [Journal Article] Classification of ligand molecules in PDB with graph match-based structural superposition. (2016)
  • Author(s): Shionyu-Mitsuyama, C., Hijikata, A., Tsuji, T. & Shirai, T.
  • Journal Title: J Struct Funct Genomics. Volume: 17 Pages: 135-146
  • Peer Reviewed
• [Journal Article] Structural and functional analyses of Barth syndrome-causing mutations and alternative splicing in the tafazzin acyltransferase domain. (2015)
  • Author(s): Hijikata A., Yura K., Ohara O., Go M.
  • Journal Title: Meta Gene Volume: 4 Pages: 92-106
  • DOI: 10.1016/j.mgene.2015.04.001
  • Peer Reviewed / Open Access
• [Presentation] タンパク質超分子複合体構造から読み解くミスセンス変異と疾患表現型との関係 (2017)
  • Author(s): 土方敦司、辻敏之、塩生真史、白井剛
  • Organizer: 第５回NGS現場の会
  • Invited
• [Presentation] 超分子複合体から読み解くミスセンス変異と疾患表現型の関係 (2017)
  • Author(s): 土方敦司、辻敏之、塩生真史、白井剛
  • Organizer: 第17回日本蛋白質科学会年会
• [Presentation] Structural and functional analysis of the C-terminal region of FliG, an essential motor component of Vibrio Na+-driven flagellar by NMR spectroscopy and molecular dynamics simulation (2017)
  • Author(s): 土方敦司、宮ノ入洋平、西野優紀、郷原瑞樹、尾上靖宏、小嶋誠司、児嶋長次郎、白井剛、甲斐荘正恒、本間道夫
  • Organizer: 公開シンポジウム「運動超分子マシナリーが織りなす調和と多様性」
• [Presentation] Towards predicting functional consequences of genetic variants in humans through supramolecular complex structures (2017)
  • Author(s): 土方敦司、辻敏之、塩生真史、白井剛
  • Organizer: 第５５回日本生物物理学会年会
• [Presentation] Decoding disease-causing mechanisms of missense mutations from supramolecular structures (2017)
  • Author(s): 土方敦司、辻敏之、塩生真史、白井剛
  • Organizer: 第6回生命医薬情報連合大会(IIBMP2017)
• [Presentation] Mutation@A Glance: ヒト遺伝子バリアント統合可視化ツール (2017)
  • Author(s): 土方敦司、白井剛
  • Organizer: トーゴーの日シンポジウム2017
• [Presentation] 分子動力学とNMRで迫るべん毛モーターの回転方向制御機構 (2017)
  • Author(s): 土方敦司
  • Organizer: 平成29年度日本分光学会NMR分光部会講習会
  • Invited
• [Presentation] Mutation@A Glance: ヒトにおける意義不明バリアントの解明を目指した統合解析ツール (2017)
  • Author(s): 土方敦司、白井剛
  • Organizer: 2017年度生命科学系合同年次大会(ConBio2017)
• [Presentation] アミノ酸残基相互作用ベクトルマッチに基づくタンパク質―低分子ドッキング法 (2016)
  • Author(s): 土方敦司、塩生真史、白井 剛
  • Organizer: 第16回日本蛋白質科学会年会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
• [Presentation] A new approach for protein-ligand binding predictions based on matching of vector-presented amino acid residues (2016)
  • Author(s): Hijikata A, Shionyu M, Shirai T
  • Organizer: 第５回生命医薬情報学連合大会
  • Place of Presentation: 東京国際交流館プラザ平成（東京都江東区）
• [Presentation] ベクトル表現化したアミノ酸残基のマッチングによるタンパク質―リガンド結合予測 (2016)
  • Author(s): 土方敦司、塩生真史、白井 剛
  • Organizer: 第54回日本生物物理学会年会
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
• [Presentation] タンパク質の高次構造から読み解く遺伝性疾患多様性メカニズム (2016)
  • Author(s): 土方 敦司, 辻 敏之, 塩生 真史, 白井 剛
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜国際平和会議場（神奈川県横浜市）
• [Presentation] TafazzinトランスアシラーゼドメインにおけるBarth症候群関連変異と選択的スプライシングの構造および機能に関する影響 (2015)
  • Author(s): 土方敦司、由良敬、小原收、郷通子
  • Organizer: 第３８回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-03
• [Remarks] ヒト疾患を引き起こすミスセンス変異の発症メカニズムの一端を解明
  • URL: http://www.nagahama-i-bio.ac.jp/research/
• [Remarks] 細菌のべん毛モーターの回転方向制御機構の一端を解明
  • URL: http://www.nagahama-i-bio.ac.jp/research/
• [Remarks] Mutation@A Glance
  • URL: http://harrier.nagahama-i-bio.ac.jp/mutation/