Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy

Gyulia Ascadi; Steven Moore; Angélique Chéron; Olivier Delalande; Lindsey Benett; William Kupsky; Mohamad El-Baba; Elisabeth Le Rumeur; Jean-Francois Hubert

doi:10.1074/jbc.M111.284521

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Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy

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Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy

Gyulia Ascadi, Steven Moore, Angélique Chéron, Olivier Delalande, Lindsey Benett, William Kupsky, Mohamad El-Baba, Elisabeth Le Rumeur and Jean-Francois Hubert

The Journal of biological chemistry, Vol.287(22), pp.18153-62

05/25/2012

DOI: 10.1074/jbc.M111.284521

PMCID: PMC3365720

PMID: 22453924

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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.

Spectrin

Immunohistochemistry

Amino Acid Sequence

Electrophoresis, Polyacrylamide Gel

Humans

Neurons and Cognition

Models, Molecular

Molecular Sequence Data

Male

Protein Folding

Sequence Homology, Amino Acid

Life Sciences

Protein Denaturation

Genetics

Muscular Dystrophy, Duchenne

Mutation

Child

Circular Dichroism

Dystrophin

Details

Title: Subtitle: Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy
Creators: Gyulia Ascadi - Connecticut Children's Medical Center
Steven Moore - Carver College of Medicine [Iowa City]
Angélique Chéron - Interactions cellulaires et moléculaires
Olivier Delalande - Interactions cellulaires et moléculaires
Lindsey Benett - Departments of Pediatrics and Neurology
William Kupsky - Departments of Pediatrics and Neurology
Mohamad El-Baba - Departments of Pediatrics and Neurology
Elisabeth Le Rumeur - Interactions cellulaires et moléculaires
Jean-Francois Hubert - Interactions cellulaires et moléculaires
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.287(22), pp.18153-62
DOI: 10.1074/jbc.M111.284521
PMID: 22453924
PMCID: PMC3365720
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology
Language: English
Date published: 05/25/2012
Academic Unit: Pathology
Record Identifier: 9984046922002771

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