Project 1: Genetic modifiers of Duchenne muscular dystrophy.

Eric P Hoffman; Robert Leshner; Children’s National Medical Center, Washington DC

Elena Pegoraro; Padova Italy

The relatively wide variation in both patient presentation and progression, and response to steroids, has long been assumed to be the result of both genetic and environmental modifiers.  Genetic modifiers, or polymorphic variants in genetic loci unlinked to the dystrophin gene, are assumed to modulate the underlying disease process.  Polymorphic loci influencing muscle structure and function are assumed to be some of the “stronger” quantitative trait loci.  This is simply due to the marked variation in muscle function between individuals.  Some individuals are inherently “strong”, some with very large muscles, some have impressive endurance.  Indeed, the Olympics can be considered a show-case of muscle genetics, as modulated by activity of the athlete.  Also, the animal husbandry field is very interested in genetic modifiers of muscle quality, due to the meat and animal sport industries.  Indeed, the most impressive muscle quantitative trait loci (QTLs) identified to date have been found in domesticated animals.  Unfortunately, animal QTLs do not directly translate to human QTLs (the nature of evolutionary conservation dictates that the genes should be conserved, while polymorphic variants are not).

What genetic modifiers have been identified to date for human muscle?  This is the focus of Project 1.  We have undertaken a study of 1,200 normal volunteers via a funded RO1, with the goal of identifying muscle QTLs in normal volunteers.  This NIH-funded study enrolls university-aged students into a 12 wk supervised resistance training intervention with the non-dominant arm.  Strength measurements are done before and after training, and muscle size is measured by MRI (again, before and after training).  The phenotypes under study are baseline size and strength, and response to training for size and strength.  To date, about 900 subjects have been recruited, trained, and phenotyped by the FAMuSS network, and about 30,000 genotypes have been done.  The finding of major QTLs in the IGF-1/AKT1 pathway, as well as validation of the ACTN3 polymorphism, serves as the preliminary data to identify genetic modifiers in Duchenne muscular dystrophy.  Importantly, the IGF-1/AKT1 pathway is known to be quite responsive to glucocorticoids, where dephosphorylation of AKT1 leads to hypophosphorylation of FOXO, and induction of the ubiquitin ligase “atrogin” gene family.  Thus, the muscle QTLs identified to date in normal subjects serve as highly likely candidates for genetic modifiers of Duchenne muscular dystrophy, and this is the focus of Project 1 (Hoffman and Escolar).  Project 1 is interdisciplinary in nature, and makes extensive use of the Cooperative International Neuromuscular Research Group (CINRG), a 24-site international clinical trial network based in the Research Center for Genetic Medicine at Children’s National Medical Center.