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.

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

“…deletions of exons 45-47, 45-48, 45-49 and 45-51 and the in vitro biochemical status of the proteins [76]. We showed that the structure of the new dystrophins as produced in these BMD patients could partly explain the differences in the clinical severity of the patients.…”

Identification of two novel Duchenne muscular dystrophies mutations in patients with Becker muscular dystrophy

“…The patients could survive until very old ages or some of them could die from an early heart failure [8,9]. Although the underlying mechanism of this variability is not fully understood, it is likely that both levels and functionality of the internally deleted dystrophins play a significant role [10]. Anthony et al [11] suggested that the patients with BMD who have milder phenotypes have higher expression levels of dystrophin.…”

“…If the dystrophin levels are greater than the threshold level (about 30%), then the structural characteristics of the internally deleted dystrophins, rather than the quantity of the dystrophin, could affect the phenotype [13]. Therefore, the structure modifications of dystrophin determined by the site of deletion in addition to its expression level modulate the severity of BMD [10].…”

eDystrophin : un nouvel outil dédié à une meilleure compréhension des dystrophinopathies

“…Les travaux de Chamberlain sur les micro-dystrophines et mini-dystrophines ont permis de préciser les exons néces-saires et les exons indispensables permettant de maintenir une dystrophine fonctionnelle [12]. La perte d'interaction avec ses partenaires, l'effet « modificateur » de variants sur d'autres gènes et le retentissement sur la configuration secondaire et tertiaire de la quasi-dystrophine issues de mutations non-tronquantes sont autant de pistes prometteuses qui permettront non seulement de comprendre la variabilité phénotypique au sein des dystrophinopathies [11,26] mais aussi de sélectionner les quasidystrophines les plus optimales dans le cadre du saut d'exon thérapeutique. Dans cette optique, nous avons développé eDystrophin, une banque de données librement accessible sur internet et interactive permettant non seulement de prédire les conséquences structurales des mutations du gène DMD conservant le cadre de lecture mais aussi leurs conséquences phénotypiques et protéi-ques observées chez les patients qui en sont porteurs.…”