Investigating the role of dystrophin isoform deficiency in motor function in Duchenne muscular dystrophy

Abstract

Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full‐length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not. Methods Functional outcome data from 387 DMD boys aged 4–15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis. Western blot analysis was used to study Dp427, Dp140 and Dp71 production in myogenic cells (control and DMD human), control skeletal muscle, DMD skeletal muscle from the three isoform groups and cerebral cortex from mice (wild‐type and DMD models). Grip strength and rotarod running test were studied in wild‐type mice and DMD mouse models. DMD mouse models were mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD‐null (lacking all isoforms). Results In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in Group 3 than Group 1 (P < 0.01) and 4.9 points lower in Group 3 than Group 2 (P = 0.05). Mean peak NSAA scores were 4.0 points lower in Group 3 than Group 1 (P < 0.01) and 1.6 points lower in Group 2 than Group 1 (P = 0.04). Mean four‐limb grip strength was 1.5 g/g lower in mdx52 than mdx mice (P = 0.003) and 1.5 g/g lower in DMD‐null than mdx mice (P = 0.002). Dp71 was produced in myogenic cells (control and DMD human) and skeletal muscle from humans in Groups 1 and 2 and mdx mice, but not skeletal muscle from human controls, myogenic cells and skeletal muscle from humans in Group 3 or skeletal muscle from wild‐type, mdx52 or DMD‐null mice. Conclusions Our results highlight the importance of considering expected effects of DMD mutations on dystrophin isoform production when considering patterns of DMD motor impairment and the implications for clinical practice and clinical trials. Our results suggest a complex relationship between dystrophin isoforms expressed in the brain and DMD motor function.

Age, corticosteroid treatment and site of mutations affect motor functional changes in young boys with Duchenne Muscular Dystrophy

“…The aim of this study was to use a systematic approach to establish the possible effect of these variables on the NSAA scores by subdividing the cohort according to age, site of mutation and CS treatment. In agreement with recent findings [8], we also found that patients with mutations affecting more dystrophin isoforms (Dp427, Dp140 and Dp71) achieved lower maximum scores compared to those with mutations in the first part of the gene in whom only Dp427 was involved (21.6 vs 27.0). Patients with mutations affecting Dp427 and Dp140 but not Dp71 had intermediate scores.…”

“…The variability has been reported as possibly due to a number of variables [8]. Most DMD patients start corticosteroid treatment (CS) between the age of 4 and 6 years and this may boost the possibility of an improvement.…”

“…Participants with DMD mutations involving the region upstream of intron 44 have involvement of Dp427 only, those with mutations involving the region from exon 51 to exon 62 have involvement of both Dp427 and Dp140 but not of Dp71 while those with mutations involving exon 63 and/or the region downstream of exon 63 have involvement of all three (Dp427/Dp140/ Dp71). Patients with involvement of all three isoforms are more likely to achieve lower performances on the NSAA (8) and to develop global developmental delay [15], acquiring motor skills at a later age than those with the involvement of Dp427 and Dp140 or of Dp427 only.…”

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy

“…Recent data suggest a potential relationship between DMD mutations predicted to have a differential impact on dystrophin isoform production and different patterns of motor function and age at presentation in boys with DMD, 44 and this could also play a role in genotype effects that arise during clinical trials.…”

“…In addition, other DMD genotype classes, and genetic modifiers at other loci 42,43 have been shown to impact functional outcomes and might also be important as prognostic factors in a clinical trial setting. Recent data suggest a potential relationship between DMD mutations predicted to have a differential impact on dystrophin isoform production and different patterns of motor function and age at presentation in boys with DMD, 44 and this could also play a role in genotype effects that arise during clinical trials.…”