title: Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy.
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.
authors.affiliation: 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.
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Hogarth
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital Westmead, New South Wales 2145, 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.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houweling
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital Westmead, New South Wales 2145, Australia.
authors.forename: Kristen C
authors.initials: KC
authors.lastname: Thomas
authors.affiliation: Research Centre for Genetic Medicine, Children's National Medical Centre, Washington DC 20010, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: Research Centre for Genetic Medicine, Children's National Medical Centre, Washington DC 20010, USA.|Department of Neurosciences, University of Padova, Padova 35122, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bello
authors.affiliation: Department of Neurosciences, University of Padova, Padova 35122, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.affiliation: Research Centre for Genetic Medicine, Children's National Medical Centre, Washington DC 20010, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
authors.forename: Stewart I
authors.initials: SI
authors.lastname: Head
authors.affiliation: 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.|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.
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000185:Actinin / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009154:Mutation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: C525925:Actn3 protein, mouse; D045222:Electron Transport Chain Complex Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000185:Actinin; D055372:AMP-Activated Protein Kinases; D019703:Calcineurin