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© The Rockefeller University Press, 0021-9525/2000/3/985/ $5.00
The Journal of Cell Biology, Volume 148, Number 5, March 6, 2000 985-996

Original Article

Massive Idiosyncratic Exon Skipping Corrects the Nonsense Mutation in Dystrophic Mouse Muscle and Produces Functional Revertant Fibers by Clonal Expansion

Q.L. Lua, G.E. Morrisb, S.D. Wiltonc, T. Lyc, O.V. Artem'yevad, P. Stronge, and T.A. Partridgea
a Muscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, London W12 ONN, UK
b Multi-Disciplinary Research and Innovation Centre Biochemistry Group, The North East Wales Institute, Wrexham LL11 2AW, UK
c Australian Neuromuscular Research Institute, QE II Medical Center, Nedlands, Western Australia 6009, Australia
d Division of Biochemistry, Royal Holloway College, London University, Surrey TW20 DEX, UK
e Division of Biomedical Sciences, Sheffield Hallam University, Sheffield S11WB, UK

Correspondence to: Q.L. Lu, Muscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. Tel:181-383-8261 Fax:181-383-8264 E-mail:qi.long-lu{at}csc.mrc.ac.uk.

Conventionally, nonsense mutations within a gene preclude synthesis of a full-length functional protein. Obviation of such a blockage is seen in the mdx mouse, where despite a nonsense mutation in exon 23 of the dystrophin gene, occasional so-called revertant muscle fibers are seen to contain near-normal levels of its protein product. Here, we show that reversion of dystrophin expression in mdx mice muscle involves unprecedented massive loss of up to 30 exons. We detected several alternatively processed transcripts that could account for some of the revertant dystrophins and could not detect genomic deletion from the region commonly skipped in revertant dystrophin. This, together with exon skipping in two noncontiguous regions, favors aberrant splicing as the mechanism for the restoration of dystrophin, but is hard to reconcile with the clonal idiosyncrasy of revertant dystrophins. Revertant dystrophins retain functional domains and mediate plasmalemmal assembly of the dystrophin-associated glycoprotein complex. Physiological function of revertant fibers is demonstrated by the clonal growth of revertant clusters with age, suggesting that revertant dystrophin could be used as a guide to the construction of dystrophin expression vectors for individual gene therapy. The dystrophin gene in the mdx mouse provides a favored system for study of exon skipping associated with nonsense mutations.

Key Words: reversion, dystrophin, nonsense mutation, splicing, exon mapping


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