α-Actinin-3: a novel genetic modifier of Duchenne muscular dystrophy

M.W. Hogarth,^1,2 P.J. Houweling,¹ H. Gordish-Dressman,⁴ E.P. Hoffman,⁴ S.I. Head³ and K.N. North,^1,2 ¹Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, NSW 2145, Australia, ²Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney NSW 2006, Australia, ³School of Medical Sciences, University of New South Wales, NSW 2052, Australia and ⁴Research Center For Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.

Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in deficiency of the fast muscle fibre protein, α-actinin-3, in ∼18% of the world's population (North et al., 1999). ACTN3 genotype significantly influences muscle performance in elite athletes (Yang et al., 2003) and in the general population (Clarkson et al., 2005). On this basis we hypothesized that ACTN3 genotype may contribute to the phenotypic variation in disease progression seen in DMD patients (Desguerre et al., 2009).

Analysis of the CINRG natural history cohort reveals α-actinin-3 deficient DMD patients have significantly reduced muscle strength and longer 10m walk test times at baseline, indicating lower overall muscle function. In order to investigate this further, we crossed our Actn3^−/− mouse line with the mdx model of DMD. Consistent with our findings in patients, isolated muscles from Actn3^−/− mdx mice show reduced maximum specific force and are significantly more damaged by eccentric stretching.

However, aged Actn3^−/− mdx mice show reduced accumulation of branched fibres and are protected from stretch-induced eccentric damage, suggesting that α-actinin-3 deficiency ameliorates the progression of dystrophic pathology. Preliminary longitudinal analysis of the CINRG natural history cohort suggests that α-actinin-3 deficiency is similarly protective against progression in DMD patients.

α-Actinin-3 deficiency is associated with increased calcineurin signaling which induces expression of the slow myogenic program and causes a shift towards slow, oxidative muscle metabolism. Over-expression of calcineurin can ameliorate pathology in mdx mice, suggesting that the metabolic shift associated with α-actinin-3 deficiency may underlie the protective effect observed in DMD.

Genetic modifiers have immediate importance in the stratification and analysis of results of therapeutic trials and have the potential to provide insight into the molecular pathogenesis of DMD. Our studies in Actn3^−/− mdx mice suggest that α-actinin-3 deficiency is detrimental to muscle performance in DMD at baseline, but ameliorates the progression of dystrophic pathology over time.

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Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, North K. (2003) ACTN3 genotype is associated with human elite athletic performance. The American Journal of Human Genetics 73, 627-631.

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Desguerre I, Christov C, Mayer M, Zeller R, Becane HM, Bastuji-Garin S, Leturcq F, Chiron C, Chelly J, Gherardi RK. (2009) Clinical heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of sub-phenotypes and predictive criteria by long-term follow-Up. PLoS ONE 4, e4347.