Identification of the functional genomic polymorphisms affecting mouse progressive hearing loss

• Project/Area Number: 15K18393
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory animal science
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: SEKI Yuta 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 研究員 (10615636)
• Research Collaborator: KIKKAWA Yoshiaki 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, プロジェクトリーダー (20280787) ; SHITARA Hiroshi 公益財団法人東京都医学総合研究所, 基盤技術研究センター, 主席基盤技術研究職員 (90321885)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 遺伝学 / 実験動物学 / ミオシンVI / ゲノム多型 / 有毛細胞 / 難聴 / ゲノム編集 / モデルマウス / 機能ゲノム多型 / ヒト変異模倣マウス / 進行性難聴

Outline of Final Research Achievements

The early-onset progressive hearing loss (ePHL) in heterozygotes of the wild-type and ksv allele of Myosin VI gene (Myo6) was accelerated by genetic background effect of C57BL/6J (B6) mice. To identify a polymorphism(s) associated with the ePHL, we performed a genetic mapping approach using a backcross progeny with MSM/Ms mice. This approach discovered that ePHL strongly associates with cadherin 23 gene (Cdh23), which is associated with the onset of hearing loss, on chromosome 10. We confirmed that c.753G>A genome editing of Cdh23 reduce the symptoms of ePHL in ksv/+ mice. However, the ePHL were not completely rescued by the genome editing; therefore, this result suggests that the other polymorphisms accompanying the genetic background of B6 mice contribute the severity and acceleration of ePHL in ksv/+ heterozygous mice.

Research Products

• [Journal Article] A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells (2017)
  • Author(s): Seki Yuta、Miyasaka Yuki、Suzuki Sari、Wada Kenta、Yasuda Shumpei P.、Matsuoka Kunie、Ohshiba Yasuhiro、Endo Kentaro、Ishii Rie、Shitara Hiroshi、Kitajiri Shin-ichiro、Nakagata Naomi、Takebayashi Hirohide、Kikkawa Yoshiaki
  • Journal Title: PLOS ONE Volume: 12 Issue: 8 Pages: e0183477-e0183477
  • DOI: 10.1371/journal.pone.0183477
  • NAID: 120007099799
  • Peer Reviewed / Open Access
• [Journal Article] Heterozygous mutation of Ush1g/Sans in mice causes early-onset progressive hearing loss, which is recovered by reconstituting the strain-specific mutation in Cdh23 (2016)
  • Author(s): Miyasaka Y, Shitara H, Suzuki S, Yoshimoto S, Seki Y, Ohshiba Y, Okumura K, Taya C, Tokano H, Kitamura K, Takada T, Hibino H, Shiroishi T, Kominami R, Yonekawa H, Kikkawa Y
  • Journal Title: Hum. Mol. Genet. Volume: 印刷中 Issue: 10 Pages: 2045-2059
  • DOI: 10.1093/hmg/ddw078
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] マウスにおけるミオシンVIのスプライス部位変異は蝸牛有毛細胞の頂部領域におけるアクチンネットワーク破綻に起因した感覚毛融合へと導く (2017)
  • Author(s): 関 優太，宮坂勇輝，鈴木沙理，吉川欣亮
  • Organizer: 第64回日本実験動物学会総会
• [Presentation] Myosin VI変異ヘテロ接合体が発症する進行性難聴の病態. (2016)
  • Author(s): 関 優太, 宮坂勇輝, 鈴木沙理, 吉川欣亮.
  • Organizer: 第63回日本実験動物学会総会
  • Place of Presentation: ミューザ川崎シンフォニーホール（神奈川県川崎市）
  • Year and Date: 2016-05-18
• [Presentation] Myosin VI変異体の感覚毛－細胞間融合プロセスと機能低下型アレルに起因した難聴発症 (2015)
  • Author(s): 関 優太，宮坂勇輝，鈴木沙理，吉川欣亮
  • Organizer: 第12回北海道実験動物研究会総会・学術集会
  • Place of Presentation: 北海道大学（北海道，札幌市）
  • Year and Date: 2015-07-11
• [Presentation] Myosin VI新規機能低下型アレルの解析で明らかとなった感覚毛－細胞間融合プロセスとハプロ不全 (2015)
  • Author(s): 関 優太，宮坂勇輝，鈴木沙理，吉川欣亮
  • Organizer: 第29回モロシヌス研究会
  • Place of Presentation: かんぽの宿有馬（兵庫県，神戸市）
  • Year and Date: 2015-07-03
• [Remarks] 哺乳類遺伝プロジェクトホームページ
  • URL: http://www.igakuken.or.jp/mammal/index.html