Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Marshall W Hogarth; Peter J Houweling; Kristen C Thomas; Heather Gordish-Dressman; Luca Bello; Cooperative International Neuromuscular Research Group (CINRG); Elena Pegoraro; Eric P Hoffman; Stewart I Head; Kathryn N North

doi:10.1038/ncomms14143

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

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

Authors

Collaborators

Cooperative International Neuromuscular Research Group (CINRG):
V Vishwanathan, S Chidambaranathan, W Douglas Biggar, Laura C McAdam, Jean K Mah, Mar Tulinius, Avital Cnaan, Lauren P Morgenroth, Robert Leshner, Carolina Tesi-Rocha, Mathula Thangarajh, Tina Duong, Andrew Kornberg, Monique Ryan, Yoram Nevo, Alberto Dubrovsky, Paula R Clemens, Hoda Abdel-Hamid, Anne M Connolly, Alan Pestronk, Jean Teasley, Tulio E Bertorini, Richard Webster, Hanna Kolski, Nancy Kuntz, Sherilyn Driscoll, John B Bodensteiner, Jose Carlo, Ksenija Gorni, Timothy Lotze, John W Day, Peter Karachunski, Erik K Henricson, Richard T Abresch, Craig M McDonald

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism
Actinin / deficiency
Actinin / genetics*
Animals
Calcineurin / genetics*
Calcineurin / metabolism
Disease Models, Animal
Electron Transport Chain Complex Proteins / genetics
Electron Transport Chain Complex Proteins / metabolism
Female
Gene Expression Regulation
Humans
Longitudinal Studies
Male
Mice
Mice, Inbred mdx
Mice, Knockout
Muscle Fibers, Skeletal / metabolism*
Muscle Fibers, Skeletal / pathology
Muscular Dystrophy, Duchenne / genetics*
Muscular Dystrophy, Duchenne / metabolism
Muscular Dystrophy, Duchenne / mortality
Muscular Dystrophy, Duchenne / pathology
Mutation
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
Phenotype
Signal Transduction
Survival Analysis

Substances

Actn3 protein, mouse
Electron Transport Chain Complex Proteins
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Actinin
AMP-Activated Protein Kinases
Calcineurin