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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.

Author information

1
Institute for Neuroscience and Muscle Research, The Children's Hospital Westmead, New South Wales 2145, Australia.
2
Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, New South Wales 2006, Australia.
3
School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
4
Murdoch Childrens Research Institute, Melbourne, Victoria 3052, Australia.
5
Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria 3010, Australia.
6
Research Centre for Genetic Medicine, Children's National Medical Centre, Washington DC 20010, USA.
7
Department of Neurosciences, University of Padova, Padova 35122, Italy.

Abstract

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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