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Nat Commun. 2017 Jan 31;8:14143. doi: 10.1038/ncomms14143.

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy.

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Institute for Neuroscience and Muscle Research, The Children's Hospital Westmead, New South Wales 2145, Australia.
Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, New South Wales 2006, Australia.
School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
Murdoch Childrens Research Institute, Melbourne, Victoria 3052, Australia.
Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria 3010, Australia.
Research Centre for Genetic Medicine, Children's National Medical Centre, Washington DC 20010, USA.
Department of Neurosciences, University of Padova, Padova 35122, Italy.


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.

Conflict of interest statement

E.P.H. has served on advisory committees for AVI BioPharma, Inc., as a consultant with the Gerson Lehman Group, Medacorp, and Lazard Capital, and is cofounder, board member, and shareholder of ReveraGen Biopharma. The remaining authors declare no competing financial interests.

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