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

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 Muscul...

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Bibliographic Details
Published in:Human mutation 2011-03, Vol.32 (3), p.299-308
Main Authors: Flanigan, Kevin M, Dunn, Diane M, von Niederhausern, Andrew, Soltanzadeh, Payam, Howard, Michael T, Sampson, Jacinda B, Swoboda, Kathryn J, Bromberg, Mark B, Mendell, Jerry R, Taylor, Laura E, Anderson, Christine B, Pestronk, Alan, Florence, Julaine M, Connolly, Anne M, Mathews, Katherine D, Wong, Brenda, Finkel, Richard S, Bonnemann, Carsten G, Day, John W, McDonald, Craig, Weiss, Robert B
Format: Article
Language:English
Subjects:
Becker muscular dystrophy
Becker's muscular dystrophy
Bone mineral density
Codon, Nonsense
DMD
Duchenne's muscular dystrophy
Dystrophin
Dystrophin - genetics
Exon skipping
Exons
Female
Humans
Language
Male
Muscular Dystrophy, Duchenne - genetics
Muscular Dystrophy, Duchenne - metabolism
Nonsense mutation
nonsense mutations
Phenotype
Point mutation
Regulatory sequences
RNA Splicing - genetics
Splicing
splicing motifs
Translation termination
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Summary: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. Hum Mutat 32:299-308, 2011.
ISSN:1059-7794
1098-1004
1098-1004
DOI:10.1002/humu.21426