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J Clin Med. 2019 May 10;8(5). pii: E649. doi: 10.3390/jcm8050649.

The "Usual Suspects": Genes for Inflammation, Fibrosis, Regeneration, and Muscle Strength Modify Duchenne Muscular Dystrophy.

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Department of Neurosciences, University of Padova, 35128 Padova, Italy.
Department of Neurosciences, University of Padova, 35128 Padova, Italy.


Duchenne muscular dystrophy (DMD), the most severe form of dystrophinopathy, is quite homogeneous with regards to its causative biochemical defect, i.e., complete dystrophin deficiency, but not so much with regards to its phenotype. For instance, muscle weakness progresses to the loss of independent ambulation at a variable age, starting from before 10 years, to even after 16 years (with glucocorticoid treatment). Identifying the bases of such variability is relevant for patient counseling, prognosis, stratification in trials, and identification of therapeutic targets. To date, variants in five loci have been associated with variability in human DMD sub-phenotypes: SPP1, LTBP4, CD40, ACTN3, and THBS1. Four of these genes (SPP1, LTBP4, CD40, and THBS1) are implicated in several interconnected molecular pathways regulating inflammatory response to muscle damage, regeneration, and fibrosis; while ACTN3 is known as "the gene for speed", as it contains a common truncating polymorphism (18% of the general population), which reduces muscle power and sprint performance. Studies leading to the identification of these modifiers were mostly based on a "candidate gene" approach, hence the identification of modifiers in "usual suspect" pathways, which are already known to modify muscle in disease or health. Unbiased approaches that are based on genome mapping have so far been applied only initially, but they will probably represent the focus of future developments in this field, and will hopefully identify novel, "unsuspected" therapeutic targets. In this article, we summarize the state of the art of modifier loci of human dystrophin deficiency, and attempt to assess their relevance and implications on both clinical management and translational research .


ACTN3; CD40; Duchenne muscular dystrophy; LTBP4; SPP1; THBS1; genetic modifiers; osteopontin

Conflict of interest statement

L.B. has received speaker honoraria from PTC Therapeutics, served in advisory boards for PTC Therapeutics and Sarepta Therapeutics, and participated in research sponsored by Santhera Pharmaceuticals. E.P. served in scientific advisory board or data safety monitoring board for PTC Therapeutics, Sarepta Therapeutics, Santhera Pharmaceuticals, Genzyme, Roche; received funding for travel and educational support from Genzyme and PTC Therapeutics; received funding for travel support from Santhera Pharmaceuticals; received grant support from Santhera Pharmaceuticals.

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