Hydrocephalus and Dementia due to motile cilia dysfunction

• Project/Area Number: 20H03591
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nagasaki University
• Principal Investigator: Yoshiura Koh-ichiro 長崎大学, 原爆後障害医療研究所, 教授 (00304931)
• Co-Investigator(Kenkyū-buntansha): 辻野 彰 長崎大学, 病院(医学系), 教授 (70423639)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: CFAP43 / 正常圧水頭症 / 変異解析 / モデルマウス / 発現解析 / 運動線毛 / 水頭症 / 上衣細胞 / 認知症 / 運動毛（motile cilia） / 運動繊毛 / 遺伝子発現プロファイル / 遺伝子変異

Outline of Research at the Start

motile cilia（運動繊毛）関連の遺伝子群が，日本人の水頭症・認知症のリスク因子であるかを，臨床検体を用いて検証する。同時にモデルマウスを解析することによって，医療に役立つ水頭症の病態生理を明らかにし，シャント術有効例・無効例の事前予測因子の取得，水頭症発症のリスク予測，を目標とする。

Outline of Final Research Achievements

Ependymal cells of CFAP43 gene knockout mice (KO mice) were collected by microdissection method, cDNA library was synthesized, and expression analysis was performed using a next-generation sequencer. KO mice and control mice were clearly distinguished on classification, and ontology analysis using genes with altered expression levels revealed altered expression of gene clusters related to ensheathment of neuron, telencephalon development, and negative regulation of cell differentiation.
Analysis of mutations in 96 genes construction cilia in patients with normal pressure hydrocephalus revealed truncation-type mutations with a minor allele frequency <0.01 in the general population, including the DRC1 gene, in 5 genes, and missense mutations in 19 genes.

Academic Significance and Societal Importance of the Research Achievements

線毛関連遺伝子の変異は，水頭症発生に関与することが明確に示された。上衣細胞の機能異常は神経分化関連の遺伝子群に集中し，線毛の構造異常から分化異常に至り機能不全に陥っていることが示唆された。ただし，その詳細は今後の研究を待たざるをえない。
線毛関連遺伝子の変異が，正常圧水頭症患者に多く見つかっていることは，正常圧水頭症・水頭症・認知症患者の一部が，線毛関連遺伝子異常症であることを明確に示唆しており，成人あるいは初老期に発症する遺伝病であることを世に知らしめた意義は大きい。

Research Products

• [Journal Article] PRRT2 mutation in a Japanese woman: Adult-onset focal epilepsy coexisting with movement disorders and cerebellar atrophy (2022)
  • Author(s): Motoyama Rie、Matsudaira Takashi、Terada Kiyohito、Usui Naotaka、Yoshiura Koh-ichiro、Takahashi Yukitoshi
  • Journal Title: Epilepsy & Behavior Reports Volume: 19 Pages: 100554-100554
  • DOI: 10.1016/j.ebr.2022.100554
  • Peer Reviewed / Open Access
• [Journal Article] Identification of unique DNA methylation sites in Kabuki syndrome using whole genome bisulfite sequencing and targeted hybridization capture followed by enzymatic methylation sequencing (2022)
  • Author(s): Hamaguchi Yo、Mishima Hiroyuki、Kawai Tomoko、Saitoh Shinji、Hata Kenichiro、Kinoshita Akira、Yoshiura Koh-ichiro
  • Journal Title: Journal of Human Genetics Volume: 67 Issue: 12 Pages: 711-720
  • DOI: 10.1038/s10038-022-01083-4
  • Peer Reviewed
• [Journal Article] <i>Itpr1</i> regulates the formation of anterior eye segment tissues derived from neural crest cells (2021)
  • Author(s): Kinoshita Akira、Ohyama Kaname、Tanimura Susumu、Matsuda Katsuya、Kishino Tatsuya、Negishi Yutaka、Asahina Naoko、Shiraishi Hideaki、Hosoki Kana、Tomiwa Kiyotaka、Ishihara Naoko、Mishima Hiroyuki、Mori Ryoichi、Nakashima Masahiro、Saitoh Shinji、Yoshiura Koh-ichiro
  • Journal Title: Development Volume: 148 Issue: 16 Pages: 188755-188755
  • DOI: 10.1242/dev.188755
  • Peer Reviewed / Open Access
• [Journal Article] Bile extracellular vesicles from end-stage liver disease patients show altered microRNA content (2021)
  • Author(s): Nakashiki Suguru、Miuma Satoshi、Mishima Hiroyuki、Masumoto Hiroshi、Hidaka Masaaki、Soyama Akihiko、Kanda Yasuko、Fukushima Masanori、Haraguchi Masafumi、Sasaki Ryu、Miyaaki Hisamitsu、Ichikawa Tatsuki、Takatsuki Mitsuhisa、Eguchi Susumu、Yoshiura Koh-ichiro、Nakao Kazuhiko
  • Journal Title: Hepatology International Volume: 15 Issue: 3 Pages: 821-830
  • DOI: 10.1007/s12072-021-10196-5
  • Peer Reviewed
• [Journal Article] Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome. (2021)
  • Author(s): Ishikawa T, Kimoto H, Mishima H, Yamagata K, Ogata S, Aizawa Y, Hayashi K, Morita H, Nakajima T, Nakano Y, Nagase S, Murakoshi N, Kowase S, Ohkubo K, Aiba T, Morimoto S, Ohno S, Kamakura S, Nogami A, Takagi M, Karakachoff M, Dina C, Schott JJ, Yoshiura KI, Horie M, Shimizu W, Nishimura K, Kusano K, Makita N.
  • Journal Title: Eur Heart J. Volume: 42(29) Issue: 29 Pages: 2854-2863
  • DOI: 10.1093/eurheartj/ehab254
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency (2021)
  • Author(s): Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 0-0
  • DOI: 10.1038/s41467-021-27085-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models (2021)
  • Author(s): Yoshiro Morimoto, Shinji Ono, Shintaro Yoshida, Hiroyuki Mishima, Akira Kinoshita, Takeshi Tanaka, Yoshihiro Komohara, Naohiro Kurotaki, Tatsuya Kishino, Yuji Okazaki, Hiroki Ozawa, Koh-ichiro Yoshiura, Akira Imamura
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 132-132
  • DOI: 10.1038/s41398-021-01258-1
  • NAID: 120007000270
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac Emerinopathy (2020)
  • Author(s): Ishikawa Taisuke、Ichida Fukiko、Makita Naomasa et al
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 13 Issue: 10 Pages: 1165-1174
  • DOI: 10.1161/circep.120.008712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib. (2020)
  • Author(s): Yamashita Y, Morita S, Hosoi H, Kobata H, Kishimoto S, Ishibashi T, Mishima H, Kinoshita A, Backes BJ, Yoshiura KI, Papa FR, Sonoki T, Tamura S
  • Journal Title: Int J Mol Sci. Volume: Aug 31;21(17) Issue: 17 Pages: 6314-6314
  • DOI: 10.3390/ijms21176314
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sphenoethmoidal meningoencephalocele with variable hypopituitarism: A case report and review of literature (2020)
  • Author(s): Morishima S, Maeda M, Itonaga T, Sato-Kawano N, Yoshiura KI, Ihara K.
  • Journal Title: Clinical Pediatric Endocrinology Volume: 29 Issue: 4 Pages: 183-187
  • DOI: 10.1297/cpe.29.183
  • NAID: 130007922122
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed / Open Access
• [Presentation] 長崎大学病院における遺伝カウンセリングの現状と課題 (2022)
  • Author(s): 髙尾真未，長谷川ゆり，三浦生子，松本 恵，伊達木澄人，古賀智裕，田中 彩，松尾久美，長石恵美，平間理子，森藤香奈子，佐々木規子，松本 正，吉浦孝一郎，三浦清徳
  • Organizer: 日本人類遺伝学会第66回大会/第28回日本遺伝子診療学会大会
• [Presentation] 次世代シークエンサーを用いた歌舞伎症候群の新規DNAメチル化サイトの検索 (2021)
  • Author(s): 濵口 陽，三嶋博之，河合智子，斎藤伸治，秦 健一郎，木下 晃，吉浦孝一郎．
  • Organizer: 日本人類遺伝学会第66回大会/第28回日本遺伝子診療学会大会 合同開催
• [Presentation] 新しいゲノム解析技術 ~メチル化解析~ (2020)
  • Author(s): 吉浦孝一郎
  • Organizer: 第44回日本遺伝カウンセリング学会学術集会
  • Invited
• [Presentation] PatakaraPlus: The project for individuals with Down Syndrome to develop oral and physical training and evaluation. (2020)
  • Author(s): Hiroyuki Mishima, Tetsuro Kitahara, Koh-Ichiro Yoshiura, Tomoko Komatsu, Masaichi Lee, Tatsuro Kondoh.
  • Organizer: 日本人類遺伝学会第65回大会
  • Invited