In muscle, the sarcoglycan complex is composed of four major subunits, 1, 2 3 and 4-sarcoglycan. The sarcoglycan complex interacts with dystrophin, the protein product of the Duchenne Muscular Dystrophy gene, to connect the cytoskeleton to the membrane and the extracellular matrix. Mutations in the genes encoding the sarcoglycan proteins lead to inherited forms of limb girdle muscular dystrophy frequently associated with cardiomyopathy. The phenotype from sarcoglycan gene mutations overlaps with what is seen in Duchenne muscular dystrophy. As with dystrophin gene mutations, there is considerable variability in disease onset and progression that cannot be explained by the specific allele. This is clearly seen with the Sgcg allele, 521-T, where this single mutation has been associated with a range of age of onset and progression of muscle weakness. In the first funding period, we generated mice lacking 3-sarcoglycan, Sgcg null. We found that, as with humans, Sgcg null mice also display a range of phenotype. During this second funding period, we identified that genetic background influences the severity of disease and now mapped a major modifier locus on chromosome 7. We also established a Drosophila model of muscular dystrophy and cardiomyopathy by deleting the 3/4 sarcoglycan ortholog in Drosophila. Using these models, we have outlined a pathologic sequence that initiates with membrane fragility and abnormal permeability that is secondarily following by attempted repair, and then myofiber and cardiomyocyte loss accompanied by fibrofatty deposition. We will use the conservation of sarcoglycan genes to understand functional differences between 3-sarcoglycan and 4-sarcoglycan. We plan to identify the genes responsible for dMOD1, the modifier locus on chromosome 7, and to test whether this modifier also alters the outcome in genetically distinct forms of muscular dystrophy. Finally, we will exploit the enhanced healing background of the MRL background to identify genetic regions that improve heart and muscle function in muscular dystrophy.

Public Health Relevance

Often the severity of muscular dystrophy and associated heart disease is not explained by the genetic mutation that produces the disease. We know that other genetic regions can improve or worsen the outcome in muscular dystrophy. We are conducting genetic studies to identify genes that improve muscular dystrophy because knowing these regions will help us predict better how patients will fare and also because these regions may point to new pathways for therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-H (14))
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Kaltman, Jonathan R
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Quattrocelli, Mattia; Spencer, Melissa J; McNally, Elizabeth M (2017) Outside in: The matrix as a modifier of muscular dystrophy. Biochim Biophys Acta 1864:572-579
McNally, Elizabeth M; Wyatt, Eugene J (2017) Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic. Circulation 136:979-981
McNally, Elizabeth M (2017) Gene Editing for the Heart: Correcting Dystrophin Mutations. Circ Res 121:896-898
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Quattrocelli, Mattia; McNally, Elizabeth M (2016) BMP and WNT: the road to cardiomyocytes is paved with precise modulation. Stem Cell Investig 3:21
Demonbreun, Alexis R; Quattrocelli, Mattia; Barefield, David Y et al. (2016) An actin-dependent annexin complex mediates plasma membrane repair in muscle. J Cell Biol 213:705-18
Vanhoutte, Davy; Schips, Tobias G; Kwong, Jennifer Q et al. (2016) Thrombospondin expression in myofibers stabilizes muscle membranes. Elife 5:
Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison et al. (2016) Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy. J Cardiovasc Transl Res 9:85-6
Lamar, Kay-Marie; Miller, Tamari; Dellefave-Castillo, Lisa et al. (2016) Genotype-Specific Interaction of Latent TGF? Binding Protein 4 with TGF?. PLoS One 11:e0150358
McNally, Elizabeth M; Wyatt, Eugene J (2016) Welcome to the splice age: antisense oligonucleotide-mediated exon skipping gains wider applicability. J Clin Invest 126:1236-8

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