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Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Author

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  • Marshall W. Hogarth

    (Institute for Neuroscience and Muscle Research, The Children’s Hospital Westmead
    Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney)

  • Peter J. Houweling

    (Institute for Neuroscience and Muscle Research, The Children’s Hospital Westmead
    School of Medical Sciences, University of New South Wales
    Murdoch Childrens Research Institute
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne)

  • 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
    University of Padova)

  • 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
    Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney
    Murdoch Childrens Research Institute
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne)

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.

Suggested Citation

  • Marshall W. Hogarth & Peter J. Houweling & Kristen C. Thomas & Heather Gordish-Dressman & Luca Bello & Elena Pegoraro & Eric P. Hoffman & Stewart I. Head & Kathryn N. North, 2017. "Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14143
    DOI: 10.1038/ncomms14143
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