title: Becker muscular dystrophy severity is linked to the structure of dystrophin.
abstract: In-frame exon deletions of the Duchenne muscular dystrophy (DMD) gene produce internally truncated proteins that typically lead to Becker muscular dystrophy (BMD), a milder allelic disorder of DMD. We hypothesized that differences in the structure of mutant dystrophin may be responsible for the clinical heterogeneity observed in Becker patients and we studied four prevalent in-frame exon deletions, i.e. Δ45-47, Δ45-48, Δ45-49 and Δ45-51. Molecular homology modelling revealed that the proteins corresponding to deletions Δ45-48 and Δ45-51 displayed a similar structure (hybrid repeat) than the wild-type dystrophin, whereas deletions Δ45-47 and Δ45-49 lead to proteins with an unrelated structure (fractional repeat). All four proteins in vitro expressed in a fragment encoding repeats 16-21 were folded in α-helices and remained highly stable. Refolding dynamics were slowed and molecular surface hydrophobicity were higher in fractional repeat containing Δ45-47 and Δ45-49 deletions compared with hybrid repeat containing Δ45-48 and Δ45-51 deletions. By retrospectively collecting data for a series of French BMD patients, we showed that the age of dilated cardiomyopathy (DCM) onset was delayed by 11 and 14 years in Δ45-48 and Δ45-49 compared with Δ45-47 patients, respectively. A clear trend toward earlier wheelchair dependency (minimum of 11 years) was also observed in Δ45-47 and Δ45-49 patients compared with Δ45-48 patients. Muscle dystrophin levels were moderately reduced in most patients without clear correlation with the deletion type. Disease progression in BMD patients appears to be dependent on the deletion itself and associated with a specific structure of dystrophin at the deletion site.
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Raguénès-Nicol
authors.affiliation: Inserm, U974, Université Pierre et Marie Curie-Paris 6, UM 76, CNRS, UMR 7215, Institut de Myologie, Paris 75013, France, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de Référence de Pathologie Neuromusculaire Paris-Est, Paris 75013 France.
authors.forename: Rabah
authors.initials: R
authors.lastname: Ben Yaou
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ameziane-Le Hir
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Chéron
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6251, Institut de Physique de Rennes, Rennes, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Vié
authors.affiliation: CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, 34000 Montpellier, France, Faculté de Médecine, Université Montpellier 1, 34000 Montpellier, France, Inserm U827, 34000 Montpellier, France and.
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.affiliation: Inserm, U974, Université Pierre et Marie Curie-Paris 6, UM 76, CNRS, UMR 7215, Institut de Myologie, Paris 75013, France, AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Hospitalier Cochin-Broca-Hotel-Dieu, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delalande
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hubert
authors.affiliation: Faculté de Médecine, Université Montpellier 1, 34000 Montpellier, France, Inserm U827, 34000 Montpellier, France and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tuffery-Giraud
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Giudice
authors.affiliation: Université de Rennes 1, Avenue du Professeur Léon Bernard, 35043 Rennes, France, CNRS UMR 6290, Institut de Génétique et Développement de Rennes, 35043 Rennes, France, elisabeth.lerumeur@univ-rennes1.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Le Rumeur
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology; D003001:Cloning, Molecular; D018450:Disease Progression; D016189:Dystrophin / Q000737:chemistry* / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008875:Middle Aged; D008958:Models, Molecular; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology; D017433:Protein Structure, Secondary; D016364:Reading Frames; D012189:Retrospective Studies; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D016189:Dystrophin