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, Elena Pegoraro, Eric P. Hoffman, Stewart I. Head and Kathryn N. North ()
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Marshall W. Hogarth: Institute for Neuroscience and Muscle Research, The Children’s Hospital Westmead
Peter J. Houweling: Institute for Neuroscience and Muscle Research, The Children’s Hospital Westmead
Kristen C. Thomas: Institute for Neuroscience and Muscle Research, The Children’s Hospital Westmead
Heather Gordish-Dressman: Research Centre for Genetic Medicine, Children’s National Medical Centre
Luca Bello: Research Centre for Genetic Medicine, Children’s National Medical Centre
Elena Pegoraro: University of Padova
Eric P. Hoffman: Research Centre for Genetic Medicine, Children’s National Medical Centre
Stewart I. Head: School of Medical Sciences, University of New South Wales
Kathryn N. North: Institute for Neuroscience and Muscle Research, The Children’s Hospital Westmead

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14143

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