Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Hogarth, Marshall W.; Houweling, Peter J.; Thomas, Kristen C.; Gordish‐Dressman, Heather; Bello, Luca; Vishwanathan, Vijay; Chidambaranathan, S.; Biggar, W. Douglas; McAdam, Laura; Mah, Jean K.; Tulinius, M.; Cnaan, Avital; Morgenroth, Lauren P.; Leshner, Robert T.; Tesi-Rocha, C.; Thangarajh, Mathula; Duong, Tina; Kornberg, Andrew J.; Ryan, Monique M.; Nevo, Yoram; Dubrovsky, Alberto; Clemens, Paula R.; Abdel-Hamid, Hoda; Connolly, Anne M.; Pestronk, Alan; Teasley, Jean; Bertorini, Tulio E.; Webster, Richard; Kolski, Hanna; Kuntz, Nancy L.; Driscoll, Sherilyn W.; Bodensteiner, John B.; Carlo, Jose; Gorni, Ksenija; Lotze, Timothy; Day, John W.; Karachunski, Peter; Henricson, E.; Abresch, Richard T.; McDonald, Craig; Pegoraro, Elena; Hoffman, Eric P.; Head, Stewart I.; North, Kathryn

doi:10.1038/ncomms14143

Cited by 57 publications

(72 citation statements)

References 59 publications

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“…First, we demonstrate that a common null polymorphism (R577X) in the ACTN3 (␣-actinin-3) gene protects the mdx mice from eccentric damage. Mechanistically, we show that this protection is associated with a decrease in the number and complexity of branched fibers in the Actn3 KO/ mdx double-knockout mouse (25). Second, Grace Pavlath's group have identified mouse olfactory receptor 23 (mOR23) as a molecule that regulates muscle fiber branching in mice (19).…”

Section: C672mentioning

confidence: 81%

Branched fibers from old fast-twitch dystrophic muscles are the sites of terminal damage in muscular dystrophy

Kiriaev

Kueh

Morley

et al. 2018

American Journal of Physiology-Cell Physiology

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A striking pathological feature of dystrophinopathies is the presence of morphologically abnormal branched skeletal muscle fibers. The deterioration of muscle contractile function in Duchenne muscular dystrophy is accompanied by both an increase in number and complexity of these branched fibers. We propose that when number and complexity of branched fibers reaches a critical threshold, or "tipping point," the branches in and of themselves are the site of contraction-induced rupture. In the present study, we use the dystrophic mdx mouse and littermate controls to study the prediseased dystrophic fast-twitch extensor digitorum longus (EDL) muscle at 2-3 wk, the peak myonecrotic phase at 6-9 wk, and finally, "old," at 58-112 wk. Using a combination of isolated muscle function contractile measurements coupled with single-fiber imaging and confocal microscope imaging of cleared whole muscles, we identified a distinct pathophysiology, acute fiber rupture at branch nodes, which occurs in "old" fast-twitch EDL muscle approaching the end stage of the dystrophinopathy muscle disease, where the EDL muscles are entirely composed of complexed branched fibers. This evidence supports our concept of "tipping point" where the number and extent of fiber branching reach a level where the branching itself terminally compromises muscle function, irrespective of the absence of dystrophin.

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Section: C672mentioning

confidence: 81%

Branched fibers from old fast-twitch dystrophic muscles are the sites of terminal damage in muscular dystrophy

Kiriaev

Kueh

Morley

et al. 2018

American Journal of Physiology-Cell Physiology

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“…Patients with available DNA samples were genotyped by TaqMan probes at the main known DMD modifier loci: SPP1 rs28357094, 14 LTBP4 rs10880, 15 CD40 rs1883832, 16 and ACTN3 rs1815739 17 . For tests of genotype/phenotype association, we used the same inheritance models as in published reports.…”

Section: Methodsmentioning

confidence: 99%

“…Other than glucocorticoid (GC) treatment and standards of care, 6,8,9 several genetic factors have been called into play as modifiers of DMD severity. These include “cis‐acting” modifiers, such as specific DMD mutations which may lead to the expression of minimal, but clinically relevant quantities of dystrophin 10–13 ; and “trans‐acting” modifiers, that is, polymorphisms in genes different from DMD , that may influence the pathological consequences of dystrophin deficiency 14–17 . As specific DMD mutations are now amenable to targeted molecular treatments, 18 such as “exon skipping” antisense oligonucleotides, or small molecules promoting stop codon readthrough, delineating “natural history” trajectories in corresponding subgroups are useful.…”

Section: Introductionmentioning

confidence: 99%

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Bello

D'Angelo

Villa

et al. 2020

Ann Clin Transl Neurol

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Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, 786 estimated that forced vital capacity (FVC) declined yearly by À4.2%, forced expiratory volume in 1 sec by À5.0%, and peak expiratory flow (PEF) by À2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately À6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

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“…In collaboration with the Cooperative International Neuromuscular Research Group consortium, we examined 61 young, ambulant patients with DMD to determine if ACTN3 R577X modifies their clinical measures (Hogarth et al., ). Consistent with our hypothesis, patients who were α‐actinin‐3 deficient showed reduced muscle strength and took longer to walk 10 m. Utilizing a double KO (DKO) mouse model that was deficient in both dystrophin ( mdx ) and α‐actinin‐3, we were able to explore the mechanisms responsible for this change in muscle strength and performance.…”

Section: Is the Evolutionary Loss Of Actn3 Our Gain? The Role Of α‐Acmentioning

confidence: 99%

Is evolutionary loss our gain? The role of ACTN3 p.Arg577Ter (R577X) genotype in athletic performance, ageing, and disease

et al. 2018

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A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α‐actinin‐3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species‐rich Eurasian climates suggesting that the absence of α‐actinin‐3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α‐actinin‐3. While the absence of α‐actinin‐3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α‐Actinin‐3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α‐actinin‐3 in healthy and diseased populations.

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Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Cited by 57 publications

References 59 publications

Branched fibers from old fast-twitch dystrophic muscles are the sites of terminal damage in muscular dystrophy

Branched fibers from old fast-twitch dystrophic muscles are the sites of terminal damage in muscular dystrophy

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Is evolutionary loss our gain? The role of ACTN3 p.Arg577Ter (R577X) genotype in athletic performance, ageing, and disease

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