title: DMD exon 1 truncating point mutations: amelioration of phenotype by alternative translation initiation in exon 6.
abstract: Mutations in the DMD gene result in two common phenotypes associated with progressive muscle weakness: the more severe Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy (BMD). We have previously identified a nonsense mutation (c.9G>A; p.Trp3X) within the first exon of the DMD gene, encoding the unique N-terminus of the 427-kDa muscle isoform of the dystrophin protein. Although this mutation would be expected to result in severe disease, the clinical phenotype is very mild BMD, with ambulation preserved into the seventh decade. We identify the molecular mechanism responsible for the amelioration of disease severity to be initiation of translation at two proximate AUG codons within exon 6. Analysis of large mutational data sets suggests that this may be a general mechanism of phenotypic rescue for point mutations within at least the first two exons of the DMD gene. Our results directly demonstrate, for the first time, the use of alternate translational initiation codons within the DMD gene, and suggest that dystrophin protein lacking amino acids encoded by the first five exons retains significant function.
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Gurvich
authors.forename: Baijayanta
authors.initials: B
authors.lastname: Maiti
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
authors.forename: Gaurav
authors.initials: G
authors.lastname: Aggarwal
authors.forename: Michael T
authors.initials: MT
authors.lastname: Howard
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
mesh_terms: D000818:Animals; D002460:Cell Line; D018387:Codon, Initiator / Q000235:genetics; D018389:Codon, Nonsense; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017354:Point Mutation; D014176:Protein Biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018387:Codon, Initiator; D018389:Codon, Nonsense; D016189:Dystrophin; D011993:Recombinant Fusion Proteins; D008156:Luciferases