RAN translation and repeat instabilty mechanism in non-coding repeat expansion disorders

• Project/Area Number: 26670170
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: Jichi Medical University
• Principal Investigator: Matsuura Tohru 自治医科大学, 医学部, 教授 (90402560)
• Co-Investigator(Renkei-kenkyūsha): Ishii Kazuhiro 筑波大学, 医学医療系, 准教授 (70323293)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 脆弱X随伴振戦/失調症候群 / FMR1遺伝子 / CGGリピート / 体細胞モザイク / mismatach repair遺伝子 / リピート不安定性 / 脆弱X随伴振戦・失調症候群 / FMR1遺伝子CGGリピート / 体細胞リピート不安定性 / DNAミスマッチ修復遺伝子発現 / 非翻訳領域リピート伸長 / 脆弱X 随伴振戦/失調症候群 / 非翻訳領域リピート病 / RAN translation / 脊髄小脳失調症8型 / 脆弱X随伴振戦失調症候群

Outline of Final Research Achievements

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a heritable neurological disorder caused by premutation (55-200 CGG repeats) of the Fragile-X-mental retardation 1 (FMR1) gene. The mechanism of fragile X repeat expansion is not well understood, including the somatic repeat number heterogeneity evident in distinct tissues from the same individual. Using multiple tissues from the autopsied FXTAS patient, we have analyzed the association between the degree of somatic mosacism and the expression level of mismatach repair (MMR) genes. The CGG repeat sizes ranged from 86～93 with one AGG interruption in multiple tissues. The difference of the repeat size was determined by the number of 3’CGG repeat. The repeat size correlated with the expression level of MMR genes in each tissue. However, cancerous tissues exhibited a bimodal repeat distribution despite extremely low expression of MMR genes.

Research Products

• [Journal Article] Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy (2016)
  • Author(s): 1.Chen G, Masuda A, Konishi H, Ohkawara B, Ito M, Kinoshita M, Kiyama H, Matsuura T, Ohno K.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 25317-25317
  • DOI: 10.1038/srep25317
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Developmentally-regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates (2016)
  • Author(s): 5.Mashiko T, Sakashita E, Kasashima K, Tominaga K, Kuroiwa K, NozakiY, Matsuura T, Hamamoto T, Endo H
  • Journal Title: J Biol Chem Volume: 291 Issue: 29 Pages: 14996-15007
  • DOI: 10.1074/jbc.m115.712232
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage response pathway in SCA3. (2015)
  • Author(s): Gao R, Liu Y, Silva-Fernandes A, Fang X, Paulucci-Holthauzen A, Chatterjee A, Zhang HL, Matsuura T, Choudhary S, Ashizawa T, Koeppen AH, Maciel P, Hazra TK, Sarkar PS.
  • Journal Title: PLoS Genet Volume: 11 Issue: 1 Pages: e1004834-e1004834
  • DOI: 10.1371/journal.pgen.1004834
  • Peer Reviewed / Open Access
• [Journal Article] Unique combination of hyperintense vessel sign on initial FLAIR and delayed vasoconstriction on MRA in reversible cerebral vasoconstriction syndrome: A case report. (2014)
  • Author(s): Kameda T, Namekawa M, Shimazaki H, Minakata D, Matsuura T, Nakano I
  • Journal Title: Cephalalgia Volume: 34 Issue: 13 Pages: 1093-1096
  • DOI: 10.1177/0333102414529197
  • Peer Reviewed
• [Journal Article] Clinical and genetic analysis of the first known Asian family with myotonic dystrophy type 2 (2014)
  • Author(s): Nakayama T, Nakamura H, Oya Y, Kimura T, Imahuku I, Ohno K, Nishino I, Abe K, Matsuura T.
  • Journal Title: J Hum Genet Volume: 59 Issue: 3 Pages: 129-133
  • DOI: 10.1038/jhg.2013.133
  • Peer Reviewed / Open Access
• [Journal Article] Seven amyotrophic lateral sclerosis patients diagnosed only after development of respiratory failure. (2014)
  • Author(s): Sato K, Morimoto N, Deguchi K, Ikeda Y, Matsuura T, Abe K.
  • Journal Title: J Clin Neurosci. Volume: Aug;21(8) Issue: 8 Pages: 1341-3
  • DOI: 10.1016/j.jocn.2013.11.021
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity (2014)
  • Author(s): Yamashita Y, Matsuura T, Kurosaki T, Amakusa Y, Kinoshita M, Ibi T, Sahashi K, Ohno K.
  • Journal Title: Neurobiol Disord Volume: 69 Pages: 200-205
  • DOI: 10.1016/j.nbd.2014.05.026
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A Collaborated Study of Fragile X syndrome and its related disorders for promoting clinical research in Japan (2016)
  • Author(s): Adachi K, Nakayama Y, Ishii K, Matsuura T, Goto Y, Nanba E
  • Organizer: The 15th International Fragile X Conference
  • Place of Presentation: San Antonio (USA)
  • Year and Date: 2016-07-20
  • Int'l Joint Research
• [Presentation] Inhibition of nuclear-cytoplasmic trafficking of Drb1/RBM45 induces toxic cytoplasmic aggregates (2016)
  • Author(s): Mashiko T, Sakashita E, Kasashima K, Tominaga K, Kuroiwa K, Matsuura T, Endo H
  • Organizer: The 21st Annual Meeting of the RNA Society
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-06-28
• [Presentation] Novel compound heterozygous mutations of SPG11 gene in sporadic spastic paraplegia with thin corpus callosum (2016)
  • Author(s): Shimazaki H, Matsuura T
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] A Collaborated Study of Fragile X syndrome and Fragile-X-Associated Tremor/ataxia Syndrome (FXTAS) for promoting clinical research in Japan (2016)
  • Author(s): Adachi K, Matsuura T, Ishii K, Nakayama Y, Goto Y, Nanba E
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] RNA disease mechanism in DM1 and SCA10 brain. (2015)
  • Author(s): Tohru Matsuura
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-29
  • Int'l Joint Research / Invited