Advertisement

Duchenne/Becker muscular dystrophy: From molecular diagnosis to gene therapy

  • Masafumi Matsuo
    Correspondence
    Corresponding author. Fax: (81) (78) 362-6064.
    Affiliations
    Division of Genetics, International Center for Medical Research, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650, Japan
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked muscular dystrophies. The recent isolation of the defective gene in DMD/BMD and the identification of its protein product, dystrophin, have revolutionized our ability to diagnose DMD/BMD and promoted speculation regarding the application of gene therapy. The purpose of this review is to present progress made in this area of research, with particular reference to dystrophin Kobe, which is caused by exon skipping during splicing due to the presence of an intra-exon deletion. On the basis of result of molecular analysis of dystrophin Kobe we propose a novel way of gene therapy for DMD, in which antisense oligonucleotides transform DMD into BMD phenotype by inducing exon skipping.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Emery AEH
        Duchenne muscular dystrophy.
        in: Oxford University Press, Oxford1993: 392
        • Matsuo M
        • Masumura T
        • Nishio H
        • et al.
        Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy Kobe.
        J Clin Invest. 1991; 87: 2127-2131
        • Hoffman EP
        • Kunkel LM
        Dystrophin abnormalities in Duchenne/Becker muscular dystrophy.
        Neuron. 1989; 2: 1019-1029
        • Rojas C
        • Hoffman E
        Recent advances in dystrophin research.
        Curr Opin Neurobiol. 1991; 1: 420-429
        • Hoffman E
        • Brown R
        • Kunkel L
        Dystrophin: the protein product of the Duchenne muscular dystrophy locus.
        Cell. 1987; 51: 919-928
        • Burghes AHM
        • Logan C
        • Hu X
        • et al.
        A cDNA clone from the Duchenne/Becker muscular dystrophy gene.
        Nature. 1987; 328: 434-437
        • Nishio H
        • Takeshima Y
        • Narita N
        • et al.
        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. 1994; 94: 1037-1042
        • Yamamoto H
        • Hagiwara Y
        • Mizuno Y
        • Yoshida M
        • Ozawa E
        Heterogeneity of dystrophin-associated proteins.
        J Biochem. 1993; 114: 132-139
        • Matsumura K
        • Tome F
        • Collin H
        • et al.
        Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy.
        Nature. 1992; 359: 320-322
        • Piccolo F
        • Roberds SL
        • Jeanpierre M
        • et al.
        Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity.
        Nat Genet. 1995; 10: 243-245
        • Ahn AH
        • Kunkel LM
        The structural and functional diversity of dystrophin.
        Nat Genet. 1993; 3: 283-291
        • D'Souza VN
        • thi Man N
        • Morris GE
        • et al.
        A novel dystrophin isoform is required for normal retinal electrophysiology.
        Hum Mol Genet. 1995; 4: 837-842
        • Koenig M
        • Hoffman EP
        • Bertelson CJ
        • et al.
        Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.
        Cell. 1987; 50: 509-517
        • Hu X
        • Ray P
        • Murphy E
        • Thompson M
        • Worton R
        Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotype genotype correlation.
        Am J Hum Genet. 1990; 46: 682-695
        • Monaco AP
        • Bertelson C
        • Liechti-Gallati S
        • Moser H
        • Kunkel L
        An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus.
        Genomics. 1988; 2: 90-95
        • Gillard EF
        • Chamberlain JS
        • Murphy EG
        • et al.
        Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene.
        Am J Hum Genet. 1989; 45: 507-520
        • Arahata K
        • Ishiura S
        • Ishiguro T
        • et al.
        Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide.
        Nature. 1988; 333: 861-863
        • Hoffman EP
        • Fischbeck KH
        • Brown RH
        • et al.
        Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy.
        N Engl J Med. 1988; 318: 1363-1368
        • Beggs AH
        • Koenig M
        • Boyce FM
        • Kunkel LM
        Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction.
        Hum Genet. 1990; 86: 45-48
      1. Ishigaki C, Patria SY, Nishio H, Yabe M, Matsuo M. A Japanese boy with myalgia and cramps and a novel in-frame deletion of the dystrophin gene. Neurology, in press.

        • Kitoh Y
        • Matsuo M
        • Nishio H
        • et al.
        Amplification of ten deletion-rich exons of the dystrophin gene by polymerase chain reaction shows deletions in 36 of 90 Japanese patients with Duchenne muscular dystrophy.
        Am J Med Genet. 1992; 42: 453-457
        • Cutiongco EM
        • Padilla CD
        • Takenaka K
        • et al.
        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. 1995; 59: 266-267
        • Gardner RJ
        • Bobrow M
        • Roberts RG
        The identification of point mutations in Duchenne muscular dystrophy patients by using reverse-transcription PCR and the protein truncation test.
        Am J Hum Genet. 1995; 57: 311-320
        • Hogervorest FBL
        • Cornelis RS
        • Bout N
        • et al.
        Rapid detection of BRCA1 mutations by the protein truncated test.
        Nature Genet. 1995; 10: 208-212
        • Roberts RG
        • Gardner RJ
        • Bobrow M
        Searching for the 1 in 2,400,000: a review of dystrophin gne point mutations.
        Hum Mutat. 1994; 4: 1-11
        • Hagiwara Y
        • Nishio H
        • Kitoh Y
        • et al.
        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. 1994; 54: 53-61
        • Acsadi G
        • Dickson G
        • Love D
        • et al.
        Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs.
        Nature. 1991; 352: 815-818
        • Wells D
        • Wells K
        • Walsh F
        • et al.
        Human dystrophin expression corrects the myopathic phenotype in transgenic mdx mice.
        Hum Mol Genet. 1992; 1: 35-40
        • Cox G
        • Phelps S
        • Chapman V
        • Chamberlain J
        New mdx mutation disrupts expression of muscle and nonmuscle isoforms of dystrophin.
        Nat Genet. 1993; 4: 87-93
        • Dunckley M
        • Wells D
        • Walsh F
        • Dickson G
        Direct retroviral-mediated transfer of a dystrophin minigene into mdx mouse muscle in vivo.
        Hum Mol Genet. 1993; 2: 717-723
        • Ragot T
        • Vincent N
        • Chafey P
        • et al.
        Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice.
        Nature. 1993; 361: 647-650
        • Vincent N
        • Ragot T
        • Gilgenkrantz H
        • et al.
        Long-term correction of mouse dystrophic degeneration by adenovirus-mediated transfer of a minidystrophin gene.
        Nat Genet. 1993; 5: 130-134
        • Green MR
        Pre-mRNA splicing.
        Annu Rev Genet. 1986; 20: 671-708
        • Matsuo M
        • Masumura T
        • Nakajima T
        • et al.
        A very small frame-shifting deletion within exon 19 of the Duchenne muscular dystrophy gene.
        Biochem Biophys Res Commun. 1990; 170: 963-967
        • Takeshima Y
        • Nishio H
        • Sakamoto H
        • Nakamura H
        • Matsuo M
        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. 1995; 95: 515-520
        • Tanaka K
        • Watakabe A
        • Shimura Y
        Polypurine sequences within a downstream exon function as a splicing enhancer.
        Mol Cell Biol. 1994; 14: 1347-1354
        • Barabino SML
        • Sproat BS
        • Lamond AI
        Antisense probes targeted to an internal domain in U2 snRNP specifically inhibit the second step of pre-mRNA splicing.
        Nucleic Acids Res. 1992; 20: 4457-4464
        • Dominski Z
        • Kole R
        Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides.
        in: 3rd edn. Proc Natl Acad Sci USA. 90. 1993: 8673-8677