Nonsense mutation-associated Becker muscular dystrophy: Interplay between exon definition and splicing regulatory elements within the DMD gene

Kevin M. Flanigan, Diane M. Dunn, Andrew Von Niederhausern, Payam Soltanzadeh, Michael T. Howard, Jacinda B. Sampson, Kathryn J. Swoboda, Mark B. Bromberg, Jerry R. Mendell, Laura E. Taylor, Christine B. Anderson, Alan Pestronk, Julaine M. Florence, Anne M. Connolly, Katherine D. Mathews, Brenda Wong, Richard S. Finkel, Carsten G. Bonnemann, John W. Day, Craig M McDonaldRobert B. Weiss

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.

Original languageEnglish (US)
Pages (from-to)299-308
Number of pages10
JournalHuman Mutation
Volume32
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Becker muscular dystrophy
  • DMD
  • Dystrophin
  • Exon skipping
  • Nonsense mutations
  • Splicing motifs

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Flanigan, K. M., Dunn, D. M., Von Niederhausern, A., Soltanzadeh, P., Howard, M. T., Sampson, J. B., Swoboda, K. J., Bromberg, M. B., Mendell, J. R., Taylor, L. E., Anderson, C. B., Pestronk, A., Florence, J. M., Connolly, A. M., Mathews, K. D., Wong, B., Finkel, R. S., Bonnemann, C. G., Day, J. W., ... Weiss, R. B. (2011). Nonsense mutation-associated Becker muscular dystrophy: Interplay between exon definition and splicing regulatory elements within the DMD gene. Human Mutation, 32(3), 299-308. https://doi.org/10.1002/humu.21426