Novel Mutation in Spectrin-like Repeat 1 of Dystrophin Central Domain Causes Protein Misfolding and Mild Becker Muscular Dystrophy*
| Autor: | Mohammad El-Baba, Olivier Delalande, William J. Kupsky, Angélique Chéron, Jean-François Hubert, Gyula Acsadi, Steven A. Moore, Lindsey Bennett, Elisabeth Le Rumeur |
|---|---|
| Přispěvatelé: | Connecticut Children's Medical Center, School of Medicine [University of Connecticut], University of Connecticut (UCONN), Carver College of Medicine [Iowa City], University of Iowa [Iowa City], Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Departments of Pediatrics and Neurology, Wayne State University [Detroit], This research was originally published in Journal of Biological Chemistry. Acsadi and al. A novel mutation in the spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy. Journal of Biological Chemistry. 2012. © the American Society for Biochemistry and Molecular Biology, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), De Villemeur, Hervé |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Models Molecular Protein Denaturation Protein Folding MESH: Sequence Homology Amino Acid [SDV.GEN] Life Sciences [q-bio]/Genetics MESH: Amino Acid Sequence Biochemistry MESH: Circular Dichroism Dystrophin Exon 0302 clinical medicine MESH: Child Missense mutation Spectrin Muscular dystrophy Child Peptide sequence Genetics 0303 health sciences biology Circular Dichroism MESH: Spectrin Molecular Bases of Disease Immunohistochemistry Protein folding [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Electrophoresis Polyacrylamide Gel MESH: Models Molecular musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities MESH: Mutation MESH: Protein Folding Molecular Sequence Data 03 medical and health sciences MESH: Dystrophin in frame single mutation Utrophin medicine MESH: Muscular Dystrophy Duchenne Humans [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Amino Acid Sequence Molecular Biology 030304 developmental biology [SDV.GEN]Life Sciences [q-bio]/Genetics Becker Muscular Dystrophy MESH: Humans MESH: Molecular Sequence Data Sequence Homology Amino Acid MESH: Immunohistochemistry Cell Biology medicine.disease Molecular biology MESH: Male Muscular Dystrophy Duchenne Mutation biology.protein MESH: Protein Denaturation 030217 neurology & neurosurgery MESH: Electrophoresis Polyacrylamide Gel |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, 2012, 287 (22), pp.18153-62. ⟨10.1074/jbc.M111.284521⟩ Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2012, 287 (22), pp.18153-62. ⟨10.1074/jbc.M111.284521⟩ |
| ISSN: | 0021-9258 1083-351X |
| DOI: | 10.1074/jbc.M111.284521⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|