Abstract 17937: Distinct Genetic Modifiers of Heart and Muscle Fibrosis in Muscular Dystrophy Revealed by Whole Genome Scan
Background: Mutations in a number of different single genes lead to cardiomyopathy and muscular dystrophy. Despite identical gene mutations, there is often significant variability in human patients that affects age of onset and severity of cardiac and skeletal muscle disease progression. In mice, this phenotypic variability is modeled by breeding into genetically distinct background strains. Mice null for the dystrophin associated protein gamma-sarcoglycan (Sgcg null) develop cardiomyopathy and muscular dystrophy. It was previously shown that cardiac and muscle fibrosis was enhanced in this model in the DBA/2J (D2-Sgcg) background and was suppressed in 129Sv/J background (129-Sgcg).
Methods: To evaluate genetic modifiers that alter cardiac fibrosis in Sgcg null mice, we generated an F2 intercross of D2-Sgcg and 129-Sgcg and employed quantitative trait locus (QTL) mapping. Using a cohort of 282 F2 mice, we analyzed multiple skeletal muscle groups and the cardiac ventricles for fibrosis by measuring hydroxyproline content to reflect collagen deposition. F2 mice were genotyped using 330 markers distributed across the genome. HOP content per tissue was associated with genetic markers using R/QTL.
Results: We found that fibrotic content in the limb based skeletal quadriceps muscle linked to a region on chromosome 7 (LOD = 6.8). This region is known to contain Ltbp4, a TGFbeta binding protein. In contrast, cardiac ventricle fibrosis showed significant linkage to a region on chromosome 9 (LOD = 4.1). Fibrosis in the diaphragm and abdominal muscles, both axial muscles, showed linkage to chromosome 3 (LOD = 7.3, LOD = 5.2).
Conclusions: These findings underscore that the same pathological trait, fibrosis, is modified differently between heart and muscle in a mouse model of muscular dystrophy. These differences may reflect physiological and/or developmental functions.
- © 2010 by American Heart Association, Inc.