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.
Skip Nav Destination
Article navigation
6 March 2000
Article|
March 06 2000
Massive Idiosyncratic Exon Skipping Corrects the Nonsense Mutation in Dystrophic Mouse Muscle and Produces Functional Revertant Fibers by Clonal Expansion
Q.L. Lu,
Q.L. Lu
aMuscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, London W12 ONN, UK
Search for other works by this author on:
G.E. Morris,
G.E. Morris
bMulti-Disciplinary Research and Innovation Centre Biochemistry Group, The North East Wales Institute, Wrexham LL11 2AW, UK
Search for other works by this author on:
S.D. Wilton,
S.D. Wilton
cAustralian Neuromuscular Research Institute, QE II Medical Center, Nedlands, Western Australia 6009, Australia
Search for other works by this author on:
T. Ly,
T. Ly
cAustralian Neuromuscular Research Institute, QE II Medical Center, Nedlands, Western Australia 6009, Australia
Search for other works by this author on:
O.V. Artem'yeva,
O.V. Artem'yeva
dDivision of Biochemistry, Royal Holloway College, London University, Surrey TW20 DEX, UK
Search for other works by this author on:
P. Strong,
P. Strong
eDivision of Biomedical Sciences, Sheffield Hallam University, Sheffield S11WB, UK
Search for other works by this author on:
T.A. Partridge
T.A. Partridge
aMuscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, London W12 ONN, UK
Search for other works by this author on:
Q.L. Lu
aMuscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, London W12 ONN, UK
G.E. Morris
bMulti-Disciplinary Research and Innovation Centre Biochemistry Group, The North East Wales Institute, Wrexham LL11 2AW, UK
S.D. Wilton
cAustralian Neuromuscular Research Institute, QE II Medical Center, Nedlands, Western Australia 6009, Australia
T. Ly
cAustralian Neuromuscular Research Institute, QE II Medical Center, Nedlands, Western Australia 6009, Australia
O.V. Artem'yeva
dDivision of Biochemistry, Royal Holloway College, London University, Surrey TW20 DEX, UK
P. Strong
eDivision of Biomedical Sciences, Sheffield Hallam University, Sheffield S11WB, UK
T.A. Partridge
aMuscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, London W12 ONN, UK
Abbreviations used in this paper: DAP, dystrophin-associated protein; DMD, Duchenne muscular dystrophy; RF, revertant fiber; RT, reverse transcription.
Received:
November 30 1999
Revision Requested:
January 24 2000
Accepted:
January 31 2000
Online ISSN: 1540-8140
Print ISSN: 0021-9525
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Cell Biol (2000) 148 (5): 985–996.
Article history
Received:
November 30 1999
Revision Requested:
January 24 2000
Accepted:
January 31 2000
Citation
Q.L. Lu, G.E. Morris, S.D. Wilton, T. Ly, O.V. Artem'yeva, P. Strong, T.A. Partridge; Massive Idiosyncratic Exon Skipping Corrects the Nonsense Mutation in Dystrophic Mouse Muscle and Produces Functional Revertant Fibers by Clonal Expansion. J Cell Biol 6 March 2000; 148 (5): 985–996. doi: https://doi.org/10.1083/jcb.148.5.985
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your InstitutionEmail alerts
Advertisement
Advertisement