Elucidation of the molecular pathogenesis of mitochondrial disease

• Project/Area Number: 16K09973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Juntendo University (2018); Saitama Medical University (2016-2017)
• Principal Investigator: Kishita Yoshihito 順天堂大学, 医学(系)研究科(研究院), 助教 (20634398)
• Research Collaborator: OKAZAKI Yasushi ; OHTAKE Akira ; MURAYAMA Kei
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ミトコンドリア / ミトコンドリア病 / 疾患原因遺伝子 / 遺伝性疾患 / アクチン / 疾患遺伝子

Outline of Final Research Achievements

Mitochondrial diseases are inherited metabolic diseases that occur when mitochondria fail to produce enough energy. In the field of pediatrics, causes of mitochondrial diseases and affected organs are particularly diverse, and the mechanism of pathogenesis may differ depending on the causative gene. To elucidate the pathogenic mechanism of mitochondrial diseases, I analyzed the molecular basis of mitochondrial diseases and searched for novel disease-causing genes. I focused on filamin genes that have been identified by previous whole exome sequencing. I have seen the abnormality of actin organization in filamin deficient cells. I have reported C1QBP and TOP3A as novel disease-causing genes.

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリア病は先天代謝異常症のなかで最も患者数の多い疾患であるが、現在までにミトコンドリア病の有効な治療法が確立されておらず、また発症原因やその分子メカニズムも十分に明らかになっていない。基盤的な分子メカニズムの理解は創薬や治療法開発に不可欠な要素であるが、本研究では新たな疾患発症メカニズムの一端を明らかにすることができた。疾患の基盤的分子メカニズムの理解が今後、創薬や治療の分子標的を見出す研究へと展開されることが期待される。

Research Products

• [Int'l Joint Research] Helmholtz Zentrum Munchen(ドイツ)
• [Journal Article] Mitochondrial complex deficiency by novel compound heterozygous TMEM70 variants and correlation with developmental delay, undescended testicle, and left ventricular noncompaction in a Japanese patient: A case report (2019)
  • Author(s): Hirono Keiichi、Ichida Fukiko、Nishio Natsuhito、Ogawa-Tominaga Minako、Fushimi Takuya、Feichtinger Rene′ G.、Mayr Johannes A.、Kohda Masakazu、Kishita Yoshihito、Okazaki Yasushi、Ohtake Akira、Murayama Kei
  • Journal Title: Clinical Case Reports Volume: 7 Issue: 3 Pages: 553-557
  • DOI: 10.1002/ccr3.2050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background. (2019)
  • Author(s): Imai-Okazaki A, Kishita Y, Kohda M, Mizuno Y, Fushimi T, Matsunaga A, Yatsuka Y, Hirata T, Harashima H, Takeda A, Nakaya A, Sakata Y, Kogaki S, Ohtake A, Murayama K, Okazaki Y.
  • Journal Title: Int J Cardiol Volume: 279 Pages: 115-121
  • DOI: 10.1016/j.ijcard.2019.01.017
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome. (2019)
  • Author(s): Borna NN, Kishita Y, Kohda M, Lim SC, Shimura M, Wu Y, Mogushi K, Yatsuka Y, Harashima H, Hisatomi Y, Fushimi T, Ichimoto K, Murayama K, Ohtake A, Okazaki Y.
  • Journal Title: Neurogenetics Volume: 20(1) Issue: 1 Pages: 9-25
  • DOI: 10.1007/s10048-018-0561-9
  • Peer Reviewed
• [Journal Article] Mutations in TOP3A Cause a Bloom Syndrome-like Disorder (2018)
  • Author(s): Martin CA, Sarlos K, Logan CV, Thakur RS, Parry DA, Bizard AH, Leitch A, Cleal L, Ali NS, Al-Owain MA, Allen W, Altmuller J, Aza-Carmona M, Barakat BAY, Barraza-Garcia J, Begtrup A, Bogliolo M, Cho MT, Cruz-Rojo J, Dhahrabi HAM, Elcioglu NH; GOSgene, Gorman GS, Jobling R, Kesterton I, Kishita Y et al
  • Journal Title: The American Journal of Human Genetics Volume: 103 Issue: 2 Pages: 221-231
  • DOI: 10.1016/j.ajhg.2018.07.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation (2018)
  • Author(s): Miyauchi Akihiko、Osaka Hitoshi、Nagashima Masako、Kuwajima Mari、Monden Yukifumi、Kohda Masakazu、Kishita Yoshihito、Okazaki Yasushi、Murayama Kei、Ohtake Akira、Yamagata Takanori
  • Journal Title: Brain and Development Volume: 40 Issue: 6 Pages: 498-502
  • DOI: 10.1016/j.braindev.2018.02.007
  • Peer Reviewed
• [Journal Article] Barth syndrome: Different approaches to diagnosis (2018)
  • Author(s): Imai-Okazaki A, Kishita Y, Kohda M, Yatsuka Y, Hirata T, Mizuno Y, Harashima H, Hirono K, Ichida F, Noguchi A, Yoshida M, Tokorodani C, Nishiuchi R, Takeda A, Nakaya A, Sakata Y, Murayama K, Ohtake A, & Okazaki Y
  • Journal Title: Journal of Pediatrics Volume: 193 Pages: 256-260
  • DOI: 10.1016/j.jpeds.2017.09.075
  • Peer Reviewed / Open Access
• [Journal Article] Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients (2017)
  • Author(s): Ogawa Erika、Shimura Masaru、Fushimi Takuya、Tajika Makiko、Ichimoto Keiko、Matsunaga Ayako、Tsuruoka Tomoko、Ishige Mika、Fuchigami Tatsuo、Yamazaki Taro、Mori Masato、Kohda Masakazu、Kishita Yoshihito、Okazaki Yasushi、Takahashi Shori、Ohtake Akira、Murayama Kei
  • Journal Title: Journal of Inherited Metabolic Disease Volume: 40 Issue: 5 Pages: 685-693
  • DOI: 10.1007/s10545-017-0042-6
  • Peer Reviewed
• [Journal Article] Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies (2017)
  • Author(s): Feichtinger RG, Olahova M, Kishita Y, Garone C, Kremer LS, Yagi M, Uchiumi T, Murayama K, Ohtake A, Rebelo-Guiomar P, Kohda M, Kang D, Mayr JA, Taylor RW, Okazaki Y, Minczuk M, Prokisch H et al
  • Journal Title: The American Journal of Human Genetics Volume: 101 Issue: 4 Pages: 525-538
  • DOI: 10.1016/j.ajhg.2017.08.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel mutation in TAZ causes mitochondrial respiratory chain disorder without cardiomyopathy (2016)
  • Author(s): Borna NN, Kishita Y, Ishikawa K, Nakada K, Hayashi JI, Tokuzawa Y, Kohda M, Nyuzuki H, Yamashita-Sugahara Y, Nasu T, Takeda A, Murayama K, Ohtake A, Okazaki Y
  • Journal Title: J Hum Genet Volume: 62 Issue: 5 Pages: 539-547
  • DOI: 10.1038/jhg.2016.165
  • NAID: 40021210340
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dried blood spots for newborn screening allows easy determination of a high heteroplasmy rate in severe infantile cardiomyopathy (2016)
  • Author(s): Imai A, Kishita Y, Nakayama Y, Fujita S, Futatani T, Kohda M, Yatsuka Y, Nakaya A, Sakata Y, Murayama K, Ohtake A, Okazaki Y
  • Journal Title: International Journal of Cardiology Volume: 221 Pages: 446-449
  • DOI: 10.1016/j.ijcard.2016.06.287
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DNM1L-related encephalopathy in infancy with Leigh syndrome-like phenotype and suppression-burst. (2016)
  • Author(s): Zaha K, Matsumoto H, Itoh M, Saitsu H, Kato K, Kato M, Ogata S, Murayama K, Kishita Y, Mizuno Y, Kohda M, Nishino I, Ohtake A, Okazaki Y, Matsumoto N, Nonoyama S.
  • Journal Title: Clinical Genetics Volume: 90 Issue: 5 Pages: 472-474
  • DOI: 10.1111/cge.12805
  • Peer Reviewed
• [Presentation] Association between mutations in genes encoding non-mitochondrial proteins and pathogenesis of mitochondrial diseases (2018)
  • Author(s): Kishita Y，Kohda M，Fushimi T, Yatsuka Y, Lim SC，Borna NN, Hirata T, Imai-Okazaki A，Matsunaga A, Shimura M, Tajika M, Kuranobu N, Ichimoto K, Harashima H，Murayama K，Ohtake A, Okazaki Y
  • Organizer: AussieMit2018
  • Int'l Joint Research
• [Presentation] Homozygous mutation in MIC13 impairs cristae structure and causes mitochondrial DNA depletion syndrome (2018)
  • Author(s): Kishita Y, Kohda M, Akita M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Shimura M, Murayama K, Ohtake A, Okazaki Y
  • Organizer: Keystone symposia -Mitochondrial biology (Z1)
  • Int'l Joint Research
• [Presentation] Identification of novel disease-causing genes associated with mitochondrial dynamics in mitochondrial disorders (2018)
  • Author(s): Kishita Y, Kohda M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Shimura M, Murayama K, Ohtake A, Okazaki Y
  • Organizer: 1st International Mitochondria Meeting for Young Scientists
  • Int'l Joint Research
• [Presentation] Genetic background of Japanese patients with mitochondrial disorders (2017)
  • Author(s): Kishita Y, Kohda M, Mizuno Y, Imai A, Nakaya A, Hirata T, Yatsuka Y, Borna NN, Harashima H, Murayama K, Ohtake A, Okazaki Y
  • Organizer: EUROMIT2017
  • Int'l Joint Research
• [Presentation] ミトコンドリア病における他の疾患を引き起こす遺伝子変異の発見 (2017)
  • Author(s): 木下 善仁，神田 将和，八塚由紀子，平田 智子，水野 洋介，今井-岡﨑 敦子，原嶋 宏子，村山 圭，大竹 明，岡﨑 康司
  • Organizer: 第59回日本先天代謝異常学会総会/第15回 アジア先天代謝異常症シンポジウム
  • Int'l Joint Research
• [Presentation] Identification of mutations in non-mitochondrial disease genes in mitochondrial diseases (2017)
  • Author(s): Kishita Y, Kohda M, Yatsuka Y, Hirata T, Mizuno Y, Imai-Okazaki A, Harashima H, Murayama K, Ohtake A, Okazaki Y
  • Organizer: 第15回RCGMフロンティアシンポジウム
• [Presentation] Mitochondrial DNA depletion syndrome caused by homozygous mutation in MIC13 (2016)
  • Author(s): Kishita Y, Kohda M, Akita M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Yamazaki T, Shimura M, Murayama K, Ohtake A, Okazaki Y
  • Organizer: 第1４回RCGMフロンティア国際シンポジウム
  • Place of Presentation: 埼玉医科大学創立３０周年記念講堂(埼玉県日高市)
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Mitochondrial DNA depletion syndrome caused by homozygous mutation in MIC13 (2016)
  • Author(s): Kishita Y, Kohda M, Akita M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Yamazaki T, Shimura M, Murayama K, Ohtake A, Okazaki Y
  • Organizer: The 13th Conference of Asian Society for Mitochondrial Research and Medicine [ASMRM]
  • Place of Presentation: TKPガーデンシティ品川(東京都港区)
  • Year and Date: 2016-10-30
• [Presentation] Comprehensive genomic analysis identified mutations in nuclear-encoded mitochondria-related gene impairing mitochondrial fission and fusion balance (2016)
  • Author(s): Kishita Y, Suzuki S, Tokuzawa Y, Nyuzuki H, Kohda M, Murayama K, Ohtake A, Okazaki Y
  • Organizer: Keystone Symposia -Mitochondrial Dynamics (D2)
  • Place of Presentation: Sheraton Steamboat Resort (Steamboat Springs, Colorado,USA)
  • Year and Date: 2016-04-03
  • Int'l Joint Research