| First Author | Hogarth MW | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Pages | 14143 | PubMed ID | 28139640 |
| Mgi Jnum | J:245032 | Mgi Id | MGI:5913811 |
| Doi | 10.1038/ncomms14143 | Citation | Hogarth MW, et al. (2017) Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy. Nat Commun 8:14143 |
| abstractText | 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 alpha-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that alpha-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. |
