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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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Nicolas A,Raguénès-Nicol C,Ben Yaou R,Ameziane-Le Hir S,Chéron A,Vié V,Claustres M,Leturcq F,Delalande O,Hubert JF,Tuffery-Giraud S,Giudice E,Le Rumeur E,French Network of Clinical Reference Centres for Neuromuscular Diseases (

doi

10.1093/hmg/ddu537

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

1267-79

issue

eissn

0964-6906

issn

1460-2083

pii

ddu537

journal_volume

pub_type

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Becker muscular dystrophy severity is linked to the structure of dystrophin.