Correlation between cis-acing elements and effects on inducing exon skipping

• Project/Area Number: 23591496
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kobe University
• Principal Investigator: YAGI Mariko 神戸大学, 医学(系)研究科(研究院), 研究員 (60362787)
• Co-Investigator(Kenkyū-buntansha): TAKESHIMA Yasuhiro 神戸大学, 大学院医学研究科, 教授 (40281141) ; AWANO Hiroyuki 神戸大学, 大学院医学研究科, 特命助教 (30437470)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: スプライシング / 国際情報研究 / 国際情報交流

Research Abstract

Antisense oligonucleotides that induce exon skipping is now attracting much attention to express internally deleted-dystrophin in Duchenne muscular dystrophy(DMD). Previously, we identified antisense oligonucleotides(AO85) that could induce exon 45 skipping efficiently. We examined the ability of AO85 to induce exon 45 skipping and dystrophin expression in DMD patient-derived myocytes carrying different types of deletion mutations, as follows:exon 46-47, 46-48, 46-49, 46-51 or 46-53. The skipping efficiency was different from patients to patients. We identified the junction site of each patient with deletion mutation and examined the intronic splicing enhancers/silencers (ISEs/ISSs) in the junction site. In this study, we could not clarify the correlation between ISEs/ISSs in the junction site and exon 45 skipping efficiency.

Research Products

• [Journal Article] A novel splicing silencer generated by DMD exon 45 deletion junction could explain upstream exon 44 skipping that modifies dystrophinopathy (2014)
  • Author(s): Dwianingsih EK, Malueka R, Nishida A, Lee T, Yagi M, Iijima K, Takeshima Y, Ito K, Matsuo M
  • Journal Title: J Hum Genet Volume: (in press)
  • Peer Reviewed
• [Journal Article] A novel splicing silencer generated by DMD exon 45 deletion junction could explain upstream exon 44 skipping that modifies dystrophinopathy. (2014)
  • Author(s): Ery Kus Dwianingsih, Rusdy Malueka, Atsuhiro Nishida, Tomoko Lee, Mariko Yagi, Kazumoto Iijima, Yasuhiro Takeshima, Kyoko Ito, Masafumi Matsuo.
  • Journal Title: J Hum Genet. Volume: in press
  • Peer Reviewed
• [Journal Article] Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients. (2013)
  • Author(s): Lee T, Takeshima Y, Kusunoki N, Awano H, Yagi M, Matsuo M, Iijima K.
  • Journal Title: J Hum Genet. Volume: 59 Issue: 1 Pages: 46-51
  • DOI: 10.1038/jhg.2013.119
  • NAID: 40019946811
  • Peer Reviewed
• [Journal Article] A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old. (2013)
  • Author(s): Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, Iijima K, Takeshima Y, Urade Y, Matsuo M.
  • Journal Title: Clin Chim Acta. Volume: 423 Pages: 10-14
  • DOI: 10.1016/j.cca.2013.03.031
  • Peer Reviewed
• [Journal Article] Molecular characterization of an X(p21.2;q28) chromosomal inversion in a Duchenne muscular dystrophy patient with mental retardation reveals a novel long non-coding gene on Xq28. (2013)
  • Author(s): Thu Tran TH, Zhang Z, Yagi M, Lee T, Awano H, Nishida A, Okinaga T, Takeshima Y, Matsuo M.
  • Journal Title: J Hum Genet Volume: 58 Issue: 1 Pages: 33-39
  • DOI: 10.1038/jhg.2012.131
  • NAID: 10031145898
  • Peer Reviewed
• [Journal Article] Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers (2012)
  • Author(s): Rusdy Ghazali Malueka, Yutaka Takaoka, Mariko Yagi, Hiroyuki Awano, Tomoko Lee, Ery Kus Dwianingsih, Atsushi Nishida, Yasuhiro Takeshima, Masafumi Matsuo
  • Journal Title: BMC Genetics Volume: 13(23) Issue: 1 Pages: 23-23
  • DOI: 10.1186/1471-2156-13-23
  • Peer Reviewed
• [Journal Article] Optimizing RNA/ENA chimeric antisense oligonucleotides using in vitro splicing. (2012)
  • Author(s): Takeshima Y, Yagi M, Matsuo M.
  • Journal Title: Methods Mol Biol. Volume: 867 Pages: 131-141
  • DOI: 10.1007/978-1-61779-767-5_9
  • ISBN: 9781617797668, 9781617797675
  • Peer Reviewed
• [Journal Article] A G-to-T transversion at the splice acceptor site of dystrophin exon 14 shows multiple splicing outcomes that are not exemplified by transition mutations. (2012)
  • Author(s): Ota M, Takeshima Y, Nishida A, Awano H, Lee T, Yagi M, Matsuo M.
  • Journal Title: Genet Test Mol Biomarkers. Volume: 16 Issue: 1 Pages: 3-8
  • DOI: 10.1089/gtmb.2010.0276
  • Peer Reviewed
• [Journal Article] A Japanese child with geleophysic dysplasia caused by a novel mutation of FBN1. (2012)
  • Author(s): Lee T, Takeshima Y, Okizuka Y, Hamahira K, Kusunoki N, Awano H, Yagi M, Sakai N, Matsuo M, Iijima K
  • Journal Title: Gene Volume: 512 Issue: 2 Pages: 456-459
  • DOI: 10.1016/j.gene.2012.10.060
  • Peer Reviewed
• [Journal Article] Antisense oligonucleotide induced dystrophin exon 45 skipping at a low half-maximal effective concentration in a cell-free splicing system (2011)
  • Author(s): Malueka RG, Yagi M, Awano H, Lee T, Dwianingsih EK, Nishida A, Takeshima Y, Matsuo M
  • Journal Title: Nucleic Acid Ther Volume: 21(5) Issue: 5 Pages: 347-53
  • DOI: 10.1089/nat.2011.0310
  • Peer Reviewed
• [Journal Article] Chemical treatment enhances skipping of a mutated exon in the dystrophin gene (2011)
  • Author(s): Nishida A, Kataoka N, Takeshima Y,Yagi M, Awano, H, Ota, M, Itoh K, Hagiwara M, and Matsuo M
  • Journal Title: Nat Commun Volume: 2 Issue: 1 Pages: 308-308
  • DOI: 10.1038/ncomms1306
  • NAID: 120003001398
  • Peer Reviewed
• [Journal Article] Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. (2011)
  • Author(s): Nishida A, Kataoka N,
  • Journal Title: Nature Communications Volume: 2 Pages: 308-308
  • Peer Reviewed
• [Journal Article] Antisense oligonucleotide induced dystrophin exon 45 skipping at a low half-maximal effective concentration in a cell-free splicing system. (2011)
  • Author(s): Malueka RG
  • Journal Title: Nucleic Acid Ther Volume: 21 Pages: 347-353
  • Peer Reviewed
• [Presentation] ジストロフィン遺伝子スプライシングコンセンサス配列内変異によるスプライシング型の変化に関わる因子の検討 (2013)
  • Author(s): 李知子、楠典子、八木麻理子、竹島泰弘、松尾雅文、飯島一誠
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 宮城県仙台市
• [Presentation] ジストロフィン遺伝子スプライシングコンセンサス配列内変異によるスプライシング型の変化 に関わる因子の検討 (2013)
  • Author(s): 李知子、楠典子、八木麻理子、竹島泰弘、松尾雅文、飯島一誠、
  • Organizer: 日本人類遺伝学会第５８回大会
  • Place of Presentation: 宮城県仙台市
• [Presentation] A small chemical, TG003, enhances skipping of mutated dystrophin exons : the third example revealing a decrease of exonic splicing enhancer density in common (2012)
  • Author(s): Nishida A, Takeshima Y, Kataoka N, Yagi M, Awano H, Lee T, Iijima K, Hagiwara M, Matsuo M
  • Organizer: The American Society of Human Genetics, the 62th Annual Meeting
  • Place of Presentation: San Francisco
• [Presentation] Duchenne/Becker型筋ジストロフィーにおけるジストロフィン遺伝子の微小変異の割合は増加傾向にある (2012)
  • Author(s): 李知子、楠典子、粟野宏之、八木麻理子、竹島泰弘、松尾雅文、飯島一誠
  • Organizer: 日本人類遺伝学会57回大会
  • Place of Presentation: 東京
• [Presentation] Dystrophin gene mutations in three dystrophinopathy patients with severe cardiomyopathy (2012)
  • Author(s): Awano H, Lee T, Yagi M, Takeshima Y, Matsuo M, Iijima K
  • Organizer: Pediatric Academic Societies Annual Meeting
  • Place of Presentation: Boston
• [Presentation] A small chemical, TG003, enhances skipping of mutated dystrophin exons: the third example revealing a decrease of exonic splicing enhancer density in common. (2012)
  • Author(s): Nishida A, Takeshima Y, Kataoka N, Yagi M, Awano H, Lee T, Iijima K, Hagiwara M, Matsuo M.
  • Organizer: The American Society of Human Genetics, the 62th Annual Meeting
  • Place of Presentation: San Francisco
• [Presentation] Duchenne/Becker型筋ジストロフィー兄弟例における心機能障害の検討 (2012)
  • Author(s): 李知子、粟野宏之、八木麻理子、竹島泰弘、松尾雅文、飯島一誠
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] Duchenne型筋ジストロフィーにおける尿プロスタグランディンD2代謝産物の排泄の増加 (2012)
  • Author(s): 中川卓、李知子、粟野宏之、八木麻理子、松尾雅文、竹島泰弘
  • Organizer: 第54回日本小児神経学会総会
  • Place of Presentation: 札幌
• [Presentation] Duchenne/Becker型筋ジストロフィーにおけるジストロフィン遺伝子の微小変異の割合は増加傾向にある (2012)
  • Author(s): 李知子、楠典子、粟野宏之、八木麻理子、竹島泰弘、松尾雅文、飯島一誠
  • Organizer: 日本人類遺伝学会第57回大会
  • Place of Presentation: 東京
• [Presentation] ベサフィブラートにより骨格筋症状が改善した極長鎖アシルCoA脱水素酵素欠損症の1例 (2012)
  • Author(s): 八木麻理子、楠典子、李知子、粟野宏之、但馬剛、小林弘典、長谷川有紀、山口清次、竹島泰弘、飯島一誠
  • Organizer: 第54回日本先天代謝異常学会
  • Place of Presentation: 岐阜
• [Presentation] Antisense RNA/Ethylene-bridged nucleic acid chimera induces exon 45 skipping in cultured myocytes from DMD patients with 6 different deletion mutaions (2011)
  • Author(s): Yagi M, Lee T, Awano H, Takeshima Y, Matsuo M
  • Organizer: The American Society of Human Genetics 61th Annual Meeting
  • Place of Presentation: Montreal
• [Presentation] ジストロフィン遺伝子エクソンスキッピングを誘導する低分子化合物の同定と治療への応用 (2011)
  • Author(s): 八木麻理子、李知子、粟野宏之、伊東恭子、竹島泰弘、松尾雅文
  • Organizer: 第53回日本小児神経学会総会
  • Place of Presentation: 横浜
• [Presentation] Antisense RNA/Ethylene-bridged nucleic acid chimera induces exon 45 skipping in cultured myocytes from DMD patients with 6 different deletion mutaions. (2011)
  • Author(s): Yagi M,
  • Organizer: The American Society of Human Genetics 61th Annual Meeting
  • Place of Presentation: Montreal
• [Presentation] MLPA法を用いたジストロフィン遺伝子解析のピットフォール (2011)
  • Author(s): 粟野宏之
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 千葉
• [Book] Treatment of Duchenne muscular dystrophy by induction of exon skipping with antisense oligonucleotides In Fifty years of neuromuscular disorder research after discovery of creatine kinase as a diagnostic marker of muscular dystrophy. (2011)
  • Author(s): Matsuo M,
  • Publisher: IGAKU-SHOIN