Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy
AuthorHogarth, MW; Houweling, PJ; Thomas, KC; Gordish-Dressman, H; Bello, L; Pegoraro, E; Hoffman, EP; Head, SI; North, KN
Source TitleNature Communications
PublisherNATURE PUBLISHING GROUP
Document TypeJournal Article
CitationsHogarth, M. W., Houweling, P. J., Thomas, K. C., Gordish-Dressman, H., Bello, L., Pegoraro, E., Hoffman, E. P., Head, S. I. & North, K. N. (2017). Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy. Nature Communications, 8 (1), https://doi.org/10.1038/ncomms14143.
Access StatusOpen Access
Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.
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