Titre :
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A novel mutation in the R1 domain of dystrophin causes protein missfolding and a mild form of becker muscular dystrophy
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contenu dans :
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Auteurs :
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4th International Congress of Myology, 4ème colloque international de Myologie (9-13 mai 2011; Lille (France)) ;
Hubert JF ;
Moore S ;
Delalande O ;
Chéron A ;
Bennett L ;
Kupski W ;
El-Baba M ;
Le Rumeur E ;
Ascadi G
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Type de document :
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Article
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Année de publication :
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2011
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Pages :
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p. 72
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Langues:
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Anglais
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Résumé :
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Missense mutations in the dystrophin gene often lead to Becker muscular dystrophy (BMD) but genotype/phenotype correlation is difficult to establish. Amino acid substitutions even in the repeat region of dystrophin may disrupt binding capacities of dystrophin and have a major impact on the functionality this protein. We have identified a family with two young brothers having very mild proximal weakness, recurrent abdominal pain and moderately elevated serum creatine kinase levels (3,000 IU). An immunostaining approach for evaluating dystrophin expression was performed on a muscle biopsy. Dystrophin immunofluorescence showed absent to weak staining for dystrophin regions encoded by exons 7 to 9. A T>C transition at codon 427 in the dystrophin gene causing a Leu>Pro amino acid change in the first spectrin-like repeat (R1) was identified as a novel mutation. We carried out in vitro biophysical analysis and molecular modelling of a two-repeat portion of the dystrophin rod domain bearing the mutation (R1-2 vs R1-2 L427P). There was no change in the lipid binding capacity of R1- 2 dystrophin peptides containing the patient's mutation. However, significant alteration in thermal and chemical folding behavior was observed. We conclude that in frame mutation in the R1 spectrin-like domain can affect the folding properties of dystrophin protein and lead to a milder variant of BMD.
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