Molecular functional analysis of ZBTB10, the novel candidate deafness gene associated with cochlear nerve hypoplasia

• Project/Area Number: 15K10773
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: 独立行政法人国立病院機構(東京医療センター臨床研究センター)
• Principal Investigator: Mutai Hideki 独立行政法人国立病院機構(東京医療センター臨床研究センター), その他部局等, 研究員 (60415891)
• Co-Investigator(Kenkyū-buntansha): 難波 一徳 独立行政法人国立病院機構(東京医療センター臨床研究センター), その他部局等, 研究員 (60425684)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 内耳奇形 / 蝸牛神経 / 難聴遺伝子 / 神経芽腫細胞 / ゲノム編集 / 胎生致死

Outline of Final Research Achievements

We have identified ZBTB10 as a candidate of novel deafness gene from a patient with cochlear nerve hypoplasia using whole exome analysis. ZBTB10 appeared to be expressed in the cochlear nerve. ZBTB10 expression was increased during nerve elongation of neuroblastoma NB1 cells. Zbtb10mut/+ mouse generated by CRISPR/Cas9 showed normal hearing. Low reproduction rate and anatomical observation suggests that the gene also affect proper function of ovary. All the Zbtb10mut/mut and half the number of Zbtb10mut/+ embryos seemed to be dead by the embryonic day 14.5 (E14.5). Zbtb10 appeared to be critical for early embryogenesis. We are now conducting histochemical study focusing on development of the brain, otocyst, and primordial germ line cells at E9.5. We will accumulate, analyze the data and report the results to the public soon.

Research Products

• [Journal Article] High-level heteroplasmy for the m.7445A>G mitochondrial DNA mutation can cause progressive sensorineural hearing loss in infancy. (2018)
  • Author(s): Matsushima K, Nakano A, Arimoto Y, Mutai H, Yamazawa K, Murayama K, Matsunaga T.
  • Journal Title: Intl J Ped Otorhinolaryng Volume: 108 Pages: 125-131
  • DOI: 10.1016/j.ijporl.2018.02.037
  • Peer Reviewed
• [Journal Article] Spontaneous intramural duodenal hematoma as the manifestation of Noonan syndrome. (2018)
  • Author(s): Yamazawa K, Yamada Y, Kuroda T, Mutai H, Matsunaga T, Komiyama O, Takahashi T.
  • Journal Title: Am J Med Genet A Volume: 176 Issue: 2 Pages: 496-498
  • DOI: 10.1002/ajmg.a.38556
  • Peer Reviewed
• [Journal Article] Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss. (2017)
  • Author(s): Yamamoto N, Mutai H, Namba K, Morita N, Masuda S, Nishi Y, Nakano A, Masuda S, Fujioka M, Kaga K, Ogawa K, Matsunaga T.
  • Journal Title: Orphanet J Rare Dis Volume: 25;12(1) Issue: 1 Pages: 157-157
  • DOI: 10.1186/s13023-017-0708-z
  • Peer Reviewed / Open Access
• [Journal Article] Homozygous EDNRB Mutation in a Patient with Waardenburg Syndrome Type 1 (2017)
  • Author(s): Noriko Morimoto, Hideki Mutai, Kazunori Namba, Hiroki Kaneko, Rika Kosaki, Tatsuo Matsunaga
  • Journal Title: Auris Nasus Larynx Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Microbiomes of The Normal Middle Ear and Chronic Otitis Media (2017)
  • Author(s): Shujiro B. Minami, Hideki Mutai, Tomoko Suzuki Arata Horii, Naoki Oishi, Koichiro Wasano, Motoyasu Katsura, Fujinobu Tanaka, Tetsuya Takiguchi, Masato Fujii, Kimitaka Kaga
  • Journal Title: Laryngoscope Volume: 印刷中 Issue: 10
  • DOI: 10.1002/lary.26579
  • Peer Reviewed
• [Journal Article] WFS1 and GJB2 mutations in patients with bilateral low-frequency sensorineural hearing loss (2017)
  • Author(s): Natsuko Kasakura-Kimura, Masatsugu Masuda, Hideki Mutai, Sawako Masuda, Noriko Morimoto, Noboru Ogahara, Hayato Misawa, Hirokazu Sakamoto, Koichiro Saito, Tatsuo Matsunaga
  • Journal Title: Laryngoscope Volume: 印刷中 Issue: 9
  • DOI: 10.1002/lary.26528
  • Peer Reviewed
• [Journal Article] Mitochondrial mutations in maternally inherited hearing loss (2017)
  • Author(s): Hideki Mutai, Takahisa Watabe, Kenjiro Kosaki, Kaoru Ogawa and Tatsuo Matsunaga
  • Journal Title: BMC Medical Genetics Volume: 18 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s12881-017-0389-4
  • Peer Reviewed / Open Access
• [Journal Article] Frequency and Specific Characteristics of the Incomplete Partition Type III Inner Ear Anomaly in Children with Hearing Loss (2017)
  • Author(s): Ayako Kanno, Hideki Mutai, Kazunori Namba, Noriko Morita, Atsuko Nakano, Noboru Ogahara, Tomoko Sugiuchi, Kaoru Ogawa, Tatsuo Matsunaga
  • Journal Title: Laryngoscope Volume: 印刷中 Issue: 7 Pages: 1663-1669
  • DOI: 10.1002/lary.26245
  • Peer Reviewed
• [Journal Article] A novel nonsense mutation in the NOG gene causes familial NOG-related symphalangism spectrum disorder (2016)
  • Author(s): Kenichi Takano, Noriko Ogasawara, Tatsuo Matsunaga, Hideki Mutai, Akihiro Sakurai, Aki Ishikawa, and Tetsuo Himi
  • Journal Title: Human Genome Variation Volume: 3 Pages: 16023-16023
  • Peer Reviewed / Open Access
• [Journal Article] A novel frameshift variant of COCH supports the hypothesis that haploinsufficiency is not a cause of autosomal dominant nonsyndromic deafness 9 (2016)
  • Author(s): Masuda M, Mutai H, Arimoto Y, Nakano A, Matsunaga T
  • Journal Title: Biochem Biophys Res Commun. Volume: 469 Issue: 2 Pages: 270-274
  • DOI: 10.1016/j.bbrc.2015.11.106
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical characteristics of a Japanese family with hearing loss accompanied by compound heterozygous mutations in LOXHD1 (2016)
  • Author(s): Minami S, Mutai H, Namba M, Sakamoto H, Matsunaga T
  • Journal Title: Auris Nasus Larynx Volume: S0385-8146 Issue: 6 Pages: 30065-7
  • DOI: 10.1016/j.anl.2016.02.010
  • NAID: 130005773901
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss (2015)
  • Author(s): Wasano K, Mutai H, Obuchi C, Masuda S, Matsunaga T
  • Journal Title: Biochem Biophys Res Comm Volume: 463 Issue: 4 Pages: 582-586
  • DOI: 10.1016/j.bbrc.2015.05.099
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High prevalence of CDH23 mutation in patients with congenital high-frequency recessive or sporadic hereditary hearing loss (2015)
  • Author(s): Mizutari K, Mutai H., Namba K., Miyanaga Y., Nakano A., Arimoto Y., Masuda S., Morimoto N., Sakamoto H., Kaga K., Matsunaga T.
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 10 Issue: 1 Pages: 60-60
  • DOI: 10.1186/s13023-015-0276-z
  • Peer Reviewed / Open Access
• [Presentation] Whole Exome Sequencing to Discover Novel Genes Associated with Hearing Loss (2018)
  • Author(s): Hideki Mutai, Yukihide Momozawa, Yoichiro Kamatani, Michiaki Kubo, Tatsuo Matsunaga
  • Organizer: 41th annual midwinter meeting, Association for Research in Otolaryngology
  • Int'l Joint Research
• [Presentation] Apoptosis is Associated with Decreased BDNF Signal in the Spiral Ganglion of Otof -deficient Mouse (2018)
  • Author(s): Kazunori Namba, Hideki Mutai, Tatsuo Matsunaga
  • Organizer: 41th annual midwinter meeting, Association for Research in Otolaryngology
  • Int'l Joint Research
• [Presentation] 臨床検体を用いた中耳細菌叢のメタ16S解析 (2017)
  • Author(s): 務台英樹、鈴木朋子、南修司郎
  • Organizer: NGS現場の会 第5回研究会
• [Presentation] Exome解析を用いた新規難聴原因遺伝子の探索 (2017)
  • Author(s): 務台英樹 松永達雄
  • Organizer: 第27回日本耳科学会
• [Presentation] 臨床像を起点とした遺伝性難聴診療の確立 (2017)
  • Author(s): 松永達雄、加我君孝、務台英樹、奈良清光、南修司郎、山本修子、藤岡正人、小川郁
  • Organizer: 第27回日本耳科学会
• [Presentation] TECTA蛋白の構造解析による新規変異の分子病態予測 (2017)
  • Author(s): 山本修子、難波一徳、務台英樹、森田訓子、松永達雄
  • Organizer: 第27回日本耳科学会
• [Presentation] 混合難聴の進行により、人工内耳埋め込み術を施行した中耳・内耳奇形・内耳道狭窄の3症例の検討 (2017)
  • Author(s): 利國桂太郎、南修司郎、山本修子、和佐野浩一郎、務台英樹、松永達雄、加我君孝
  • Organizer: 第27回日本耳科学会
• [Presentation] Microbiomes in the normal middle ear and chronic otitis media (2016)
  • Author(s): Minami S, Mutai H, Suzuki T, HoriiA, Oishi N, Katsura M, Wasano K, Tanaka F, Takiguchi T, Fujii M.
  • Organizer: Association for Research in Otolaryngology 39th Midwiner Meeting
  • Place of Presentation: Manchester Grand Hyatt, San Diego, CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Exome解析を用いた症候群性難聴に対する原因遺伝子同定の試み (2015)
  • Author(s): 務台英樹、仲野敦子、有本友希子、松永達雄
  • Organizer: 第25回日本耳科学会総会
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2015-10-07
• [Book] 中耳細菌叢のメタ16S解析 in 実験医学別冊 NGSアプリケーション 今すぐ始める！メタゲノム解析 実験プロトコール 編：服部正平 (2016)
  • Author(s): 南修司郎、務台英樹
  • Total Pages: 229
  • Publisher: 羊土社