title: Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45.
abstract: OBJECTIVE
  Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre-mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion-exon 45 (Δ45)-may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients.
  
  
  METHODS
  Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions.
  
  
  RESULTS
  As expected, deletions of either exons 45 to 47 (Δ45-47) or exons 45 to 48 (Δ45-48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45-46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44-45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype.
  
  
  CONCLUSIONS
  The observation that Δ45-46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone.
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Findlay
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wein
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kaminoh
authors.forename: Laura E
authors.initials: LE
authors.lastname: Taylor
authors.forename: Diane M
authors.initials: DM
authors.lastname: Dunn
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Wendy M
authors.initials: WM
authors.lastname: King
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Julaine M
authors.initials: JM
authors.lastname: Florence
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Mathews
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Michael T
authors.initials: MT
authors.lastname: Howard
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.forename: Craig
authors.initials: C
authors.lastname: McDonald
authors.forename: Aurélie
authors.initials: A
authors.lastname: Nicolas
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Le Rumeur
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D030541:Databases, Genetic; D005091:Exons / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D010641:Phenotype; D011237:Predictive Value of Tests; D016896:Treatment Outcome; D055815:Young Adult