The molecular analysis of idiopathic normal pressure hydrocephalus as ciliarydyskinesia

• Project/Area Number: 17K10309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Kagawa University (2018-2019); Nagasaki University (2017)
• Principal Investigator: Kurotaki Naohiro 香川大学, 医学部, 教授 (20423634)
• Co-Investigator(Kenkyū-buntansha): 松坂 雄亮 長崎大学, 病院(医学系), 助教 (30728944) ; 小澤 寛樹 長崎大学, 医歯薬学総合研究科(医学系), 教授 (50260766)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 正常圧水頭症 / 認知症 / 繊毛機能不全 / 全エキソーム解析 / 全エクソーム解析 / 繊毛

Outline of Final Research Achievements

Normal-pressure hydrocephalus (NPH) is usually sporadic,but some casese were reported as familial. We found 3-generated familial cases including 4 patients and one showed several psycotic symptoms. In orde to identify responsible genes in the family, we used whole-exome sequencing (WES) and analyzed cases. We identified a loss-of-function variant in the CFAP43 gene linked to this disease in this family. Considering result of further study of Cfap43 knockout mice, we conclude mutation in CFAP43 elicits abnormalities in cilia and leads to NPH.

Academic Significance and Societal Importance of the Research Achievements

歩行障害や尿失禁を伴う認知症である、正常圧水頭症のほとんどは直接の原因がはっきしりしない孤発例であるが、私たちが偶然遭遇した症例は家族の中に複数の患者さんがいるいわゆる家族症例であった。そこで、私たちがこの症例においては何らかの遺伝子変異の影響があるのではと考え、次世代型シーケンサーを用いた全エキソーム解析を行ったところ、CFAP43遺伝子の変異が見つかったので、そのノックアウトマウスを作り、解剖学的、組織学的検索を行った。その結果、脳室や呼吸器系における繊毛の形態不全や発育不全が起きていることがわかった。これはカルタゲナー症候群と類似の病態であり今後の薬物療法の開発に示唆を与えると思われた。

Research Products

• [Journal Article] Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies. (2020)
  • Author(s): Imamura A, Morimoto Y, Ono S, Kurotaki N, Kanegae S, Yamamoto N, Kinoshita H, Tsujita T, Okazaki Y, Ozawa H.
  • Journal Title: J Neural Transm Volume: in press Issue: 11 Pages: 1501-1515
  • DOI: 10.1007/s00702-020-02188-w
  • Peer Reviewed
• [Journal Article] Activity-dependent Cleavage of Dyskinesia-Related Proline-Rich Transmembrane Protein 2 (PRRT2) by Calpain in Mouse Primary Cortical Neurons (2020)
  • Author(s): Daisuke Hatta, Keiro Shirotani , Yuma Hori, Naohiro Kurotaki, Nobuhisa Iwata
  • Journal Title: FASEB Journal Volume: 34 Issue: 1 Pages: 180-191
  • DOI: 10.1096/fj.201902148r
  • NAID: 120006988315
  • Peer Reviewed / Open Access
• [Journal Article] Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities (2019)
  • Author(s): Morimoto Y, Yoshida S, Kinoshita A, Satoh C, Mishima H, Yamaguchi N, Matsuda K, Sakaguchi M, Tanaka T, Komohara Y, Imamura A, Ozawa H, Nakashima M, Kurotaki N, Kishino T, Yoshiura K, Ono S
  • Journal Title: Neurology Volume: 92 Issue: 20
  • DOI: 10.1212/wnl.0000000000007505
  • NAID: 120006987711
  • Peer Reviewed / Open Access
• [Journal Article] Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder. Transl Psychiatry. (2018)
  • Author(s): Morimoto Y, Shimada-Sugimoto M, Otowa T, Yoshida S, Kinoshita A, Mishima H, Yamaguchi N, Mori T, Imamura A, Ozawa H, Kurotaki N, Ziegler C, Domschke K, Deckert J, Umekage T, Tochigi M, Kaiya H, Okazaki Y, Tokunaga K, Sasaki T, Yoshiura KI, Ono S.
  • Journal Title: Transl Psychiatry Volume: 8 Issue: 1 Pages: 41-41
  • DOI: 10.1038/s41398-017-0088-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease. (2017)
  • Author(s): Morimoto Y, Ono S, Imamura A, Okazaki Y, Kinoshita A, Mishima H, Nakane H, Ozawa H, Yoshiura KI, Kurotaki N.
  • Journal Title: Hum Genome Var. Volume: 4 Issue: 1 Pages: 17032-17032
  • DOI: 10.1038/hgv.2017.32
  • Peer Reviewed / Open Access