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1996 Fiscal Year Final Research Report Summary

Molecular biological study to establish the treatment for Duchenne muscular dystrophy

Research Project

Project/Area Number 06557047
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field Pediatrics
Research InstitutionKobe University

Principal Investigator

MATSUO Masafumi  Kobe University School of Medicine, Professor, 医学部, 教授 (10157266)

Co-Investigator(Kenkyū-buntansha) NISHIO Hisahide  Kobe University School of Medicine, Asso.Prof., 医学部, 助教授 (80189258)
Project Period (FY) 1994 – 1996
Keywordsdystrophin Kobe / lymphoblastoid cells / antisenseoligonucleotide / exon skipping
Research Abstract

Duchenne muscular dystrophy (DMD) is a rapid progressive disease which usually results in death at around the age of 20, while Becker muscular dystrophy (BMD) is a clinically less severe form of the disease which often has only slight debilitating effects. DMD and BMD are allelic diseases caused by mutations of the dystrophin gene, which consists of 79 exons. Deletion mutations have been identified in two thirds of DMD/BMD cases, and the clinical progression of DMD or BMD patients can be predicted from whether or not the deletion maintains or disrupts the translational reading frame of the mRNA.Gene therapy is attracting increasing attention as a plausible treatment for DMD.And reading frame displacement to correct the effects of frame-shift deletions on translation is one of approaches.
In this study we first report that exon skipping from the dystrophin gene transcript could in living cells by an antisense oligodeoxynucleotide (ODN) complementary to an exon recognition sequence (ERS). Incubation of lymphoblastoid cells with an antisense ODN against the purine-rich region of dystrophin exon 19 resulted in skipping of the exon from the dystrophin transcript. Skipping of exon 19 started to appear after 6 hours of incubation, and complete skipping was observed after 24 hours of incubation. None of the other 78 dystrophin exons were skipped, and exon 19 skipping could not be induced by the sense ODN or by an antisense ODN corresponding to another ERS.These results showed that antisense ODN against ERS induces exon skipping even in living cells. This paved the road to establish gene therapy for DMD.

  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Hagiwara, Y.: "A novel point mutation (G-1 to T) in a 5' splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker muscular dystrophy." Am. J. Hum. Genet.54. 53-61 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kitoh, Y.: "Amplification of selected exons by polymerase chain reavtion enables determination of the translational reading frame of dystrophin mRNA." Kobe. J. Med. Sci.40. 39-48 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishio, H.: "Identification of a novel first exon in the human dystrophin gene and of a new promoter located more than 500 kb upstream of the nearest known promoter." J. Clin. Invest.94. 1037-1042 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeshima, Y.: "Amino-teminal deletion of 53% of dystrophin results in an intermediate Duchenne-Becker muscular dystrophy phenotype." Neurology. 44. 1648-1651 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cutiongco, E. M.: "More deletions in the 5' region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients." Am. J. Med. Genet.59. 266-267 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuo, M.: "Duchenne muscular dystrophy." Southeast Asian J. Trop. Med. Pub. Heal, 26 Supplement. 1. 166-171 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuo, M.: "Molecular diagnosis of Duchenne muscular dystrophy." Sing. Paediat. J.37. 143-147 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Pokharel, R. K.: "A novel mutation substituting tryptophan with arginine in the carboxyl-terminal, noncollagenous domain of collagen X in a case of Schmid metaphyseal chondrodysplasia." Biochem. Biophys. Res. Commun.217. 1157-1162 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeshima, Y.: "Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe." J. Clin. Invest.95. 515-520 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka, Y.: "Developmental expression pattern of the Caenorhabditis elegans homologue of the Drosophila suppressor of forked gene." DNA Res.2. 143-146 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yu, Y.: "Cardiac Involvement in a Family with Becker muscular dystrophy." Internal Med.34. 919-923 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishigaki, C.: "A Japanese boy with myalgia and cramps and a novel in-frame deletion of the dystrophin gene." Neurology. 46. 1347-1350 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuo, M.: "Duchenne/Becker muscular dystrophy: from molecular diagnosis to gene therapy." Brain Dev.18. 167-172 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Patria, S. Y.: "A case of Becker muscular dystrophy resulting from the skipping of four contiguous exons (71-74) of the dystrophin gene during mRNA maturation." Proc. Assoc. Am. Phys.108. 308-314 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Pramono, Z. A. D.: "Induction of exon skipping of the dystrophin transcript in lymphoblastoid cells by transfecting an antisense oligodeoxynucleotide complementary to an exon recognition sequence." Biochem. Biophys. Res. Commun.226. 445-449 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Wada, H.: "Severe neonatal nemaline myopathy with delayed maturation of muscle." Brain Dev.18. 135-138 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tachi, N.: "Deficiency of syntrophin, dystroglycan, and merosin in a female infant of congenital muscular dystrophy phenotype with a lack of cystein-rich and C-terminal domains of dystrophin." Neurology. (in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Goji, K.: "A novel missense mutation in the HMG box of SOX9 gene in a Japanese XY male resulted in campomelic dysplasia and severe defect in masculinization." Hum. Mutation. (in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hagiwara, Y.: "A novel point mutation (G-1 to T) in a 5' splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker muscular dystrophy." Am.J.Hum.Genet.54. 53-61 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitoh, Y.: "Amplification of selected exons by polymerase chain reavtion enables determination of the translational reading frame of dystrophin mRNA." Kobe.J.Med.Sci.40. 39-48 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishio, H.: "Identification of a novel first exon in the human dystrophin gene and of a new promoter located more than 500 kb upstream of the nearest known promoter." J.Clin.Invest.94. 1037-1042 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeshima, Y.: "Amino-terminal deletion of 53% of dystrophin results in an intermediate Duchenne-Becker muscular dystrophy phenotype." Neurology. 44. 1648-1651 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cutiongco, E.M.: "More deletions in the 5' region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients." Am.J.Med.Genet.59. 266-267 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsuo, M.: "Duchenne muscular dystrophy." Southeast Asian J.Trop.Med.Pub.Heal. 26 Supplement 1. 166-171 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsuo, M.: "Molecular diagnosis of Duchenne muscular dystrophy." Sing.Paediat.J.37. 143-147 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Pokharel, R.K.: "A novel mutation substituting tryptophan with arginine in the carboxyl-terminal, non-collagenous domain of collagen X in a case of Schmid metaphyseal chondrodysplasia." Biochem.Biophys.Res.Commun. 217. 1157-1162 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeshima, Y.: "Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe." J.Clin.Invest.95. 515-520 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka, Y.: "Developmental expression pattern of the Caenorhabditis elegans homologue of the Drosophila suppressor of forked gene." DNA Res.2. 143-146 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yu, Y.: "Cardiac Involvement in a Family with Becker muscular dystrophy." Internal Med.34. 919-923 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishigaki, C.: "A Japanese boy with myalgia and cramps and a novel in-frame deletion of the dystrophin gene." Neurology. 46. 1347-1350 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsuo, M.: "Duchenne/Becker muscular dystrophy : from molecular diagnosis to gene therapy." Brain Dev.18. 167-172 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Patria, S.Y.: "A case of Becker muscular dystrophy resulting from the skipping of four contiguous exons (71-74) of the dystrophin gene during mRNA maturation." Proc.Assoc.Am.Phys.108. 308-314 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Pramono, Z.A.D.: "Induction of exon skipping of the dystrophin transcript in lymphoblastoid cells by transfecting an antisense oligodeoxynucleotide complementary to an exon recognition sequence." Biochem.Biophys.Res.Commun.226. 445-449 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Wada, H.: "Severe neonatal nemaline myopathy with delayd maturation of muscle." Brain.Dev.18. 135-138 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tachi, N.: "Deficiency of syntrophin, dystroglycan, and merosin in afemale infant of congenital muscular dystrophy phenotype with a lack of cystein-rich and C-terminal domains of dystrophin." Neurology. (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Goji, K.: "A novel missense mutation in the HMG box of SOX9 gene in a Japanese XY male resulted in campomelic dysplasia and severe defect in masculinization." Hum.Mutation. (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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