title: Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy.
abstract: Mutations in the dystrophin gene without disruption of the reading frame often lead to Becker muscular dystrophy, but a genotype/phenotype correlation is difficult to establish. Amino acid substitutions may disrupt binding capacities of dystrophin and have a major impact on the functionality of this protein. We have identified two brothers (ages 8 and 10 years) with very mild proximal weakness, recurrent abdominal pain, and moderately elevated serum creatine kinase levels. Gene sequencing revealed a novel mutation in exon 11 of the dystrophin gene (c.1280T>C) leading to a L427P amino acid substitution in repeat 1 of the central rod domain. Immunostaining of skeletal muscle showed weak staining of the dystrophin region encoded by exons 7 and 8 corresponding to the end of the actin-binding domain 1 and the N-terminal part of hinge 1. Spectrofluorescence and circular dichroism analysis of the domain repeat 1-2 (R1-2) revealed partial misfolding of the L427P mutated protein as well as a reduced refolding rate after denaturation. Based on computational homology models of the wild-type and mutated R1-2, a molecular dynamics study showed an alteration in the flexibility of the structure, which also strongly affects the conformational space available in the N-terminal region of the fragment. Our results suggest that this missense mutation hinders the dynamic properties of the entire N-terminal region of dystrophin.
authors.affiliation: Connecticut Children's Medical Center, Hartford, Connecticut 06106, USA.
authors.forename: Gyula
authors.initials: G
authors.lastname: Acsadi
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Angélique
authors.initials: A
authors.lastname: Chéron
authors.forename: Olivier
authors.initials: O
authors.lastname: Delalande
authors.forename: Lindsey
authors.initials: L
authors.lastname: Bennett
authors.forename: William
authors.initials: W
authors.lastname: Kupsky
authors.forename: Mohammad
authors.initials: M
authors.lastname: El-Baba
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Le Rumeur
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hubert
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002942:Circular Dichroism; D016189:Dystrophin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid; D013049:Spectrin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D016189:Dystrophin; D013049:Spectrin