Human Molecular Genetics, Vol 7, 1083-1090, Copyright © 1998 by Oxford University Press
MG Dunckley, M Manoharan, P Villiet, IC Eperon and G Dickson
Deletions and point mutations in the gene encoding the cytoskeletal protein
dystrophin and its isoforms cause either the severe progressive myopathy
Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy
(BMD), largely depending on whether the reading frame is lost or maintained
respectively. Frameshift mutations tend to result in a lack of dystrophin
at the sarcolemma, destabilization of the membrane and degeneration of
skeletal muscle. The mdx mouse is a valuable animal model of DMD as it
bears a nonsense point mutation in exon 23 of the murine DMD gene leading
to an absence of dystrophin expression in the muscle sarcolemma and
muscular dystrophy. This report represents a novel approach to correct
dystrophin deficiency at the post-transcriptional level by transfection of
muscle cells with antisense RNA. Essentially, 2'- O -methyl
oligoribonucleotides (2'OMeRNA) were delivered to the nuclei of primary mdx
myoblasts in culture. Dystrophin expression was observed in the sarcolemma
of transfected mdx myotubes after transfection by an oligonucleotide
complementary to the 3' splice site of murine dystrophin intron 22. Direct
sequencing of RT-PCR products from these cells revealed precise splicing of
exon 22 to exon 30, skipping the mutant exon and creating a novel in-frame
dystrophin transcript. As patients with comparable in- frame internal
deletions show relatively mild myopathic symptoms, this may in the future
offer a therapeutic approach for DMD, as well as for other inherited
disorders.
ARTICLES
Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides
Division of Biochemistry, Royal Holloway University of London, Egham TW20 0EX, UK. m.dunckley@rpms.ac.uk
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