In muscle, the sarcoglycan complex is composed of four major subunits, alpha, beta, gamma and delta-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, delta521-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 gamma-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 gamma/delta 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 gamma-sarcoglycan and delta-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.
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.
|Kim, Ellis Y; Page, Patrick; Dellefave-Castillo, Lisa M et al. (2016) Direct reprogramming of urine-derived cells with inducible MyoD for modeling human muscle disease. Skelet Muscle 6:32|
|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|
|Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene et al. (2015) Cardiac function in muscular dystrophy associates with abdominal muscle pathology. J Neuromuscul Dis 2:39-49|
|Vo, Andy H; McNally, Elizabeth M (2015) Modifier genes and their effect on Duchenne muscular dystrophy. Curr Opin Neurol 28:528-34|
|McNally, Elizabeth M; George Jr, Alfred L (2015) New approaches to establish genetic causality. Trends Cardiovasc Med 25:646-52|
|Gao, Quan Q; McNally, Elizabeth M (2015) The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol 5:1223-39|
|Ferlini, Alessandra; Flanigan, Kevin M; Lochmuller, Hanns et al. (2015) 204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24-26 January 2014, Naarden, The Netherlands. Neuromuscul Disord 25:184-98|
|Gao, Quan Q; Wyatt, Eugene; Goldstein, Jeff A et al. (2015) Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. J Clin Invest 125:4186-95|
|McNally, Elizabeth M; Kaltman, Jonathan R; Benson, D Woodrow et al. (2015) Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent Project Muscular Dystrophy. Circulation 131:1590-8|
|McNally, Elizabeth M; Barefield, David Y; Puckelwartz, Megan J (2015) The genetic landscape of cardiomyopathy and its role in heart failure. Cell Metab 21:174-82|
Showing the most recent 10 out of 57 publications