The comprehesive analysis of human hereditary deafness

• Project/Area Number: 17H04345
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Shinshu University
• Principal Investigator: Kitajiri Shin-ichiro 信州大学, 学術研究院医学系(医学部附属病院), 講師 (00532970)
• Co-Investigator(Kenkyū-buntansha): 宇佐美 真一 信州大学, 学術研究院医学系, 教授 (10184996) ; 喜多 知子 (嶋知子) 京都大学, 医学研究科, 研究員 (20362519) ; 西尾 信哉 信州大学, 医学部, 特任講師 (70467166) ; 大西 弘恵 京都大学, 医学研究科, 研究員 (50397634)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: DIAPH1 / CLDN14 / OTOA / MYO6 / POLD1 / EPHA2 / 遺伝性難聴 / 聴覚 / 内耳機能 / TRIOBP / リポジトリ / 新規変異 / 機能解析 / 内耳 / 難聴 / 遺伝子 / MYPT / 耳科学 / 細胞生物学 / 遺伝学

Outline of Final Research Achievements

In this study, we collected and analyzed genome samples from human deafness pedigrees. The mutation of DID domain of DIAPH1 cause loss of autoinhibition leading to deafness. We identified the first CLDN14 mutation in east Asian population, and the cochlear implantation improved the hearing. The copy number variation of OTOA was significant cause of hearing loss. The myosin VI mutants inhibit the elongation of microvilli, and presumably, stereocilia. The mutation of POLD1 cause dysfunction of DNA polymerase. EphA2 binds to pendrin, the major cause of deafness, and define the localization of the complex.

Academic Significance and Societal Importance of the Research Achievements

難聴の有病率は全ての疾病の中で2番目に高く、日常生活に支障を来す障害の原因として成人発症の難聴がトップで、かつその負担は今後さらに増加すると見込まれている（WHO, 世界疾病調査）。しかし根本的治療法がなく、多くの患者が重いハンデを背負いその社会的損失は計り知れない。難聴の病態、さらに言えば聴覚受容の分子機構には不明な点が多く、これが治療法の開発を困難としている。本研究成果は内耳がいかに音を感じるのかを分子レベルで解明するものである。かつ各分子はヒト遺伝性難聴の原因遺伝子として同定したもので、これらの知見はヒトの難聴の病態に直接応用できるものである。

Research Products

• [Int'l Joint Research] National institutes of health(米国)
• [Journal Article] POLD1 variants leading to reduced polymerase activity can cause hearing loss without syndromic features (2020)
  • Author(s): Doo-Yi Oh, Yoshihiro Matsumoto, Shin-ichiro Kitajiri, Nayoung K.D. Kim, Min Young Kim, Ah Reum Kim, Mingyu Lee, Chung Lee, Alan E. Tomkinson, Tatsuya Katsuno, So Young Kim, Hyun-Woo Shin, Jin Hee Han, Seungmin Lee, Woong-Yang Park, Byung Yoon Choi
  • Journal Title: Human Mutation Volume: 41 Issue: 5 Pages: 913-920
  • DOI: 10.1002/humu.23984
  • Peer Reviewed
• [Journal Article] Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome (2020)
  • Author(s): Li, Nishio, Naruse, Riddell, Sapski, Katsuno, Hikita, Mizapourshafiyi, Smith, Cooper, Lee, Asano, Boettger, Kruger, Wietelmann, Graumann, Day, Boyd, Offermanns, Kitajiri, Usami, Nakayama
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1343-1343
  • DOI: 10.1038/s41467-020-15198-9
  • NAID: 120006888459
  • Peer Reviewed / Open Access
• [Journal Article] Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant (2019)
  • Author(s): Tomohiro Kitano, Shin-ichiro Kitajiri, Shin-ya Nishio and Shin-ichi Usami
  • Journal Title: Int. J. Mol. Sci. Volume: 20 Issue: 18 Pages: 4579-4579
  • DOI: 10.3390/ijms20184579
  • Peer Reviewed / Open Access
• [Journal Article] Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss (2019)
  • Author(s): Sugiyama、Moteki、Kitajiri、Kitano、Nishio、Yamaguchi、Wakui、Abe、Ozaki、Motegi、Matsui、Teraoka、Kobayashi、Kosho、Usami
  • Journal Title: Genes Volume: 10 Issue: 9 Pages: 715-732
  • DOI: 10.3390/genes10090715
  • Peer Reviewed / Open Access
• [Journal Article] Differential disruption of autoinhibition and defect in assembly of cytoskeleton during cell division decide the fate of human DIAPH1-related cytoskeletopathy (2019)
  • Author(s): Kim Bong Jik、Ueyama Takehiko、Miyoshi Takushi、Lee Seungmin、Han Jin Hee、Park Hye-Rim、Kim Ah Reum、Oh Jayoung、Kim Min Young、Kang Yong Seok、Oh Doo Yi、Yun Jiwon、Hwang Sang Mee、Kim Nayoung K D、Park Woong-Yang、Kitajiri Shin-ichiro、Choi Byung Yoon
  • Journal Title: Journal of Medical Genetics Volume: 56 Issue: 12 Pages: 818-827
  • DOI: 10.1136/jmedgenet-2019-106282
  • NAID: 120007032326
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing (2019)
  • Author(s): Katsuno Tatsuya、Belyantseva Inna A.、Cartagena-Rivera Alexander X.、Ohta Keisuke、Crump Shawn M.、Omori Koichi、Ito Juichi、Frolenkov Gregory I.、Friedman Thomas B.、Kitajiri Shin-ichiro
  • Journal Title: JCI Insight Volume: 4 Issue: 12 Pages: 1-21
  • DOI: 10.1172/jci.insight.128561
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microarray analyses of otospheres derived from the cochlea in the inner ear identify putative transcription factors that regulate the characteristics of otospheres. (2017)
  • Author(s): Takehiro Iki, Michihiro Tanaka, Shin-ichiro Kitajiri, Tomoko Kita, Yuri Kawasaki, Akifumi Mizukoshi, Wataru Fujibuchi, Takayuki Nakagawa, Tatsutoshi Nakahata, Juichi Ito, Koichi Omori, Megumu K. Saito
  • Journal Title: PLoS One Volume: 12
  • NAID: 120006782202
  • Peer Reviewed / Open Access
• [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): Yuta Seki, Yuki Miyasaka, Sari Suzuki, Kenta Wada, Shumpei P. Yasuda, Kunie Matsuoka, Yasuhiro Ohshiba, Kentaro Endo, Rie Ishii, Hiroshi Shitara, Shin-ichiro Kitajiri, Naomi Nakagata, Hirohide Takebayashi, Yoshiaki Kikkawa
  • Journal Title: PLoS One Volume: 12
  • NAID: 120007099799
  • Peer Reviewed / Open Access
• [Presentation] Clinical Features of Deafness Caused by a Novel CLDN14 Variant (2020)
  • Author(s): Tomohiro Kitano, Shin-ichiro Kitajiri, Shin-ya Nishio, Shin-ichi Usami
  • Organizer: ARO The 43rd Annual MidWinter Meeting
  • Int'l Joint Research
• [Presentation] Role of TRIOBP-5 in Stereocilia Rootlet Formation and Implications for Presbycusis and Gene Therapy (2020)
  • Author(s): Belyantseva, Katsuno, Cartagena-Rivera, Ohta, Petralia, Ono, Tona, Imtiaz, Kiyonari, Fitzgerald, Abe, Ikeya, Fenollar-Ferrer, Segawa, Omori, Ito, Frolenkov, Kitajiri, Friedman
  • Organizer: ARO The 43rd Annual MidWinter Meeting
  • Int'l Joint Research
• [Presentation] Identification of Hearing-loss Associated Mutations in MYO6 and In Vitro Functional Analysis (2020)
  • Author(s): Timothy F. Day, Shin-ichiro Kitajiri, Shin-ichiro Oka, Hideaki Moteki, Shin-ya Nishio, Shin-ichi Usami
  • Organizer: ARO The 43rd Annual MidWinter Meeting
  • Int'l Joint Research
• [Presentation] ヒト遺伝性難聴より見出したMYO6遺伝子変異の細胞学的解析 (2019)
  • Author(s): 北尻真一郎、Timothy Day、岡晋一郎、西尾信哉、宇佐美真一
  • Organizer: 第29回 日本耳科学会 総会・学術講演会
• [Presentation] 日本人で初めて見出された CLDN14 変異による難聴症例 (2019)
  • Author(s): 北野友裕、北尻真一郎、西尾信哉、宇佐美真一
  • Organizer: 第29回 日本耳科学会 総会・学術講演会
• [Presentation] ACTG1変異による難聴症例の臨床像と変異型γアクチンの細胞内局在 (2019)
  • Author(s): 宮嶋 宏樹(Hiroki Miyajima)、茂木 英明(Hideaki Moteki)、Timothy Day、西尾 信哉(Shin-ya Nishio)、北尻 真一郎(Shin-ichiro Kitajiri)、宇佐美 真一(Shin-ichi Usami)
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] CNVs スクリーニングにより見出された OTOA 遺伝子変異による難聴 5 症例 (2019)
  • Author(s): 杉山 健二郎(Kenjiro Sugiyama)、北野 友裕(Tomohiro Kitano)、西尾 信哉(Shin-ya Nishio)、北尻 真一郎(Shin-ichiro Kitajiri)、茂木 英明(Hideaki Moteki)、宇佐美 真一(Shin-ichi Usami)
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] Molecular investigations of deafness-related genes ACTG1 and MYO6 in vitro (2019)
  • Author(s): Day Timothy，岡 晋一郎，宮嶋宏樹， 北尻真一郎，西尾信哉，宇佐美真一
  • Organizer: 第64回日本聴覚医学会総会・学術講演会
• [Presentation] 内耳有毛細胞の感覚毛の根の形成および聴覚におけるアクチン束化タンパク質TRIOBPの役割 (2019)
  • Author(s): 勝野, Belyantseva, Cartagena-Rivera, 太田, Crump, Petralia, 小野, 十名, Imtiaz, Rehman, 清成, 金子, Wang, 阿部, 池谷, Fenollar-Ferrer, Riordan, Wilson, Fitzgerald, 瀬川, 大森, 伊藤, Frolenkov, Friedman, 北尻
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] TRIOBP regulates the localization of molecules in the inner ear hair cell (2018)
  • Author(s): Shin-ichiro Kitajiri, Tomoko Kita, Raj K Ladher, Shin-ichi Usami
  • Organizer: Joint Annual Meeting of 51st JSDB and 70th JSCB
• [Presentation] ヒトiPS細胞を用いたミトコンドリア1555変異難聴の病態解明 (2018)
  • Author(s): 喜多知子、伊木健浩、水越彬文、宇佐美真一、北尻真一郎
  • Organizer: 第28回日本耳科学会総会・学術講演会
• [Presentation] OTOF遺伝子p.R1172Q変異による難聴発症機序の解析 (2018)
  • Author(s): 岩佐陽一郎、北尻真一郎、西尾信哉、吉村豪兼、宇佐美真一
  • Organizer: 第63回日本聴覚医学会総会・学術講演会
• [Presentation] ACTG1遺伝子変異による難聴症例の検討 (2018)
  • Author(s): 宮嶋宏樹、茂木英明、北尻真一郎、西尾信哉、村田考啓、池園哲郎、武田英彦、阿部聡子、岩崎聡、高橋優宏、内藤泰、山崎博司、神田幸彦、宇佐美真一
  • Organizer: 第63回日本聴覚医学会総会・学術講演会
• [Presentation] An Attempt to Establish In Vitro Model Using TRIOBP KO Induced Pluripotent Stem Cells (2017)
  • Author(s): Hiroe Ohnishi、Shin-ichiro Kitajiri、Xiangxin Lou、Akiko Taura、Mirei Taniguchi、Fumi Ebisu、Tatsunori Sakamoto、Norio Yamamoto、Juichi Ito1、Koichi Omori、Takayuki Nakagawa
  • Organizer: 1st International Symposium on Inner Ear Therapies, November 01-03, 2017. Marrakech, Morocco
  • Int'l Joint Research
• [Presentation] 遺伝性難聴DFNA1の原因遺伝子DIAPH1と、その変異による難聴発症メカニズムの解明 (2017)
  • Author(s): 北尻真一郎、二之湯弦、西尾信哉、三好拓志、鳥居紘子、西村幸司、菅原一真、坂田英明、Dean Thumkeo、坂口博史、渡邊直樹、宇佐美真一、齋藤尚亮、上山健彦
  • Organizer: 日本人類遺伝学会第62回大会. 2017年11月15日（水）～18日（土）、神戸
• [Presentation] 不動毛の「根」の低形成と難聴 (2017)
  • Author(s): 北尻真一郎、伊藤壽一
  • Organizer: 第27回日本耳科学会. 2017年 11月22日（水）～ 24日（金）、横浜
• [Presentation] 内耳感覚毛の「根」の形成および維持におけるTRIOBPアイソフォームの役割 (2017)
  • Author(s): Tatsuya Katsuno, Keisuke Ohta. Makoto Ikeya, Kazuya Ono, Koichi Omori, Juichi Ito, Shin-ichiro Kitajiri
  • Organizer: 第40回日本分子生物学会年会（2017年度生命科学系学会合同年次大会）. 2017年12月6日～9日、神戸ポートアイランド