Abstract
A-type lamins gene (LMNA) mutations cause an autosomal dominant inherited form of Emery-Dreifuss muscular dystrophy (EDMD). EDMD is characterized by slowly progressive muscle weakness and wasting and dilated cardiomyopathy, often leading to heart failure-related disability. EDMD is highly penetrant with poor prognosis and there is currently no specific therapy available. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. Genetic background is a well-known factor that significantly affects phenotype in several mouse models of human diseases. This phenotypic variability is attributed, at least in part, to genetic modifiers that regulate the disease process. To characterize the phenotype of A-type lamins mutation on different genetic background, we created and phenotyped C57BL/6JRj-LmnaH222P/H222P mice (C57Lmnap.H222P) and compared them with the 129S2/SvPasCrl-LmnaH222P/H222P mice (129Lmnap.H222P). These mouse strains were compared with their respective control strains at multiple time points between 3 and 10 months of age. Both contractile and electrical cardiac muscle functions, as well as survival were characterized. We found that 129Lmnap.H222P mice showed significantly reduced body weight and reduced cardiac function earlier than in the C57Lmnap.H222P mice. We also revealed that only 129Lmnap.H222P mice developed heart arrhythmias. The 129Lmnap.H222P model with an earlier onset and more pronounced cardiac phenotype may be more useful for evaluating therapies that target cardiac muscle function, and heart arrhythmias.
Highlights
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of i/slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution; ii/early contractures of the elbows, ankles, and posterior neck; and iii/cardiac conduction defects associated with dilated cardiomyopathy [1]
We found that cardiac involvement was more pronounced in the 129Lmna p.H222P mouse strain compared with the C57Lmna p.H222P mouse strain, suggesting that genetic background significantly modifies the severity of dilated cardiomyopathy linked to LMNA mutations
To assess the genetic background of the C57Lmna p.H222P and 129Lmna p.H222P mouse strains, we used a marker-assisted selection protocol (MASP) based on genome-wide analysis of genetic polymorphisms, which allows the discrimination between different strains of mice [18]
Summary
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of i/slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution; ii/early contractures of the elbows, ankles, and posterior neck; and iii/cardiac conduction defects associated with dilated cardiomyopathy [1]. Engineered mouse models of EDMD have brought valuable insights in our understanding of the molecular mechanisms of the disease [3]. They have been instrumental in the identification of signaling pathways responsible for the cardiac dysfunction and have provided invaluable tools for proposing novel treatment for this disease [4,5,6,7,8,9,10]. LmnaH222P/H222P mice were generated using a C57BL/6 background, an inbred strain and useful reductionist tool to study effects of single gene mutations, in the clinic, LMNA mutations show a strong degree of pleiotropy and understanding how genetic background influences this is likely to prove important. We found that cardiac involvement was more pronounced in the 129Lmna p.H222P mouse strain compared with the C57Lmna p.H222P mouse strain, suggesting that genetic background significantly modifies the severity of dilated cardiomyopathy linked to LMNA mutations
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