Frequency of Duchenne Muscular Dystrophy Carriers

Zatz, Mayana; Lange, Ken; Spence, Madoka

doi:10.1016/s0140-6736(77)92211-5

Cited by 29 publications

(12 citation statements)

References 8 publications

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“…A milder myopathy is the Becker muscular dystrophy; in this case, deletions inside the gene produce in frame mRNAs and consequently shorter but semifunctional dystrophin proteins (1). A third of DMD cases are the results of a de novo mutation (2,3), therefore the disease can never be eliminated through genetic screening and counseling. For this reason, many efforts are now being devoted to the development of a treatment for this disorder, and several strategies have been designed that might provide an insight into finding a cure.…”

mentioning

confidence: 99%

Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Δ48-50 DMD cells

Angelis

Sthandier

Berarducci

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

119

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Deletions and point mutations in the dystrophin gene cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. Because internal in-frame deletions in the protein produce only mild myopathic symptoms, it should be possible, by preventing the inclusion of specific mutated exon(s) in the mature dystrophin mRNA, to restore a partially corrected phenotype. Such control has been previously accomplished by the use of synthetic oligonucleotides; nevertheless, a significant drawback to this approach is caused by the fact that oligonucleotides would require periodic administrations. To circumvent this problem, we have produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. In this paper we show that antisense molecules against exon 51 splice junctions are able to direct skipping of this exon in the human DMD deletion 48 -50 and to rescue dystrophin synthesis. We also show that the highest skipping activity was found when antisense constructs against the 5 and 3 splice sites are coexpressed in the same cell. D uchenne muscular dystrophy (DMD) is an X-linked recessive disorder that affects 1 in every 3,500 males. It is characterized by the absence of the cytoskeletal dystrophin (427-kDa protein) that in turn produces a severe and progressive muscle deterioration. Most of the DMD mutations consist in deletions and point mutations in the 2.5-Mb dystrophin gene that introduce stop codons and consequently premature translation termination. A milder myopathy is the Becker muscular dystrophy; in this case, deletions inside the gene produce in frame mRNAs and consequently shorter but semifunctional dystrophin proteins (1). A third of DMD cases are the results of a de novo mutation (2, 3), therefore the disease can never be eliminated through genetic screening and counseling. For this reason, many efforts are now being devoted to the development of a treatment for this disorder, and several strategies have been designed that might provide an insight into finding a cure. One of these strategies involves the transplantation of normal myoblasts into the muscle tissues that lack this protein (4, 5), whereas the other strategy tries to restore correct expression of the dystrophin through a gene therapy approach. In this direction, several groups have tried to deliver full-length or mini cDNA copies of dystrophin into cells with the mutated gene (6-8). Even if this approach is very promising, several problems still remain to be solved, such as size capacity and transducing activity of the vector and immune response to the ''therapeutic'' gene (9).Another powerful approach of gene therapy is based on the fact that internal in-frame deletions in the protein produce only mild myopathic symptoms; therefore, it should be possible, by preventing the inclusion of specific mutated exon(s) in the mature dystrophin mRNA, to restore ...

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confidence: 99%

Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Δ48-50 DMD cells

Angelis

Sthandier

Berarducci

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

119

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“…Affected boys have difficulty rising from the floor and eventually become restricted to a wheelchair by the age of 12 years, with 90% dying before their 20th birthday because of cardiac and respiratory complications (2). A third of DMD cases are the result of a de novo mutation in the dystrophin gene (3,4), and consequently this disease can never be eradicated through genetic screening and counseling, placing additional emphasis on the need to develop a treatment for this disorder.…”

mentioning

confidence: 99%

Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse

Mann

Honeyman²,

Cheng³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

306

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Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease arising from defects in the dystrophin gene, typically nonsense or frameshift mutations, that preclude the synthesis of a functional protein. A milder, allelic version of the disease, Becker muscular dystrophy, generally arises from in-frame deletions that allow synthesis of a shorter but still semifunctional protein. Therapies to introduce functional dystrophin into dystrophic tissue through either cell or gene replacement have not been successful to date. We report an alternative approach where 2'-O-methyl antisense oligoribonucleotides have been used to modify processing of the dystrophin pre-mRNA in the mdx mouse model of DMD. By targeting 2'-O-methyl antisense oligoribonucleotides to block motifs involved in normal dystrophin pre-mRNA splicing, we induced excision of exon 23, and the mdx nonsense mutation, without disrupting the reading frame. Exon 23 skipping was first optimized in vitro in transfected H-2K(b)-tsA58 mdx myoblasts and then induced in vivo. Immunohistochemical staining demonstrated the synthesis and correct subsarcolemmal localization of dystrophin and gamma-sarcoglycan in the mdx mouse after intramuscular delivery of antisense oligoribonucleotide:liposome complexes. This approach should reduce the severity of DMD by allowing a dystrophic gene transcript to be modified, such that it can be translated into a Becker-dystrophin-like protein.

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“…Onethird of all affected males should be new mutants if the mutation rates in both sexes are the same. Zatz, Frota-Pessoa, Levy, and Peres (1976), Zatz, Lange, and Spence (1977), and Danieli, Mostacciuolo, Bonante, and Angelini, (1977) have supported Haldane's prediction in their studies of Duchenne muscular dystrophy. However, Biggs and Rizzo (1976) reported the value 0.023 for the frequency of fresh mutation among affected males for hemophilia A.…”

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confidence: 89%

Cultural inheritance of the desire for male offspring and the incidence of a sex‐linked lethal disease

Yokoyama

1981

Biodemography and Social Biology

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Frequency of Duchenne Muscular Dystrophy Carriers

Cited by 29 publications

References 8 publications

Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Δ48-50 DMD cells

Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Δ48-50 DMD cells

Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse

Cultural inheritance of the desire for male offspring and the incidence of a sex‐linked lethal disease

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