title: Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene.
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.
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA. kevin.flanigan@nationwidechildrens.org
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.forename: Diane M
authors.initials: DM
authors.lastname: Dunn
authors.forename: Andrew
authors.initials: A
authors.lastname: von Niederhausern
authors.forename: Payam
authors.initials: P
authors.lastname: Soltanzadeh
authors.forename: Michael T
authors.initials: MT
authors.lastname: Howard
authors.forename: Jacinda B
authors.initials: JB
authors.lastname: Sampson
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Mark B
authors.initials: MB
authors.lastname: Bromberg
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Laura E
authors.initials: LE
authors.lastname: Taylor
authors.forename: Christine B
authors.initials: CB
authors.lastname: Anderson
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Julaine M
authors.initials: JM
authors.lastname: Florence
authors.forename: Anne M
authors.initials: AM
authors.lastname: Connolly
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Mathews
authors.forename: Brenda
authors.initials: B
authors.lastname: Wong
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bonnemann
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.forename: Craig
authors.initials: C
authors.lastname: McDonald
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
mesh_terms: D018389:Codon, Nonsense; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; C484258:DMD protein, human; D016189:Dystrophin