Effect of genetic background on the cardiac phenotype in a mouse model of Emery-Dreifuss muscular dystrophy

摘要

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-Lmna^H222P/H222P mice (C57^Lmnap.H222P) and compared them with the 129S2/SvPasCrl-Lmna^H222P/H222P mice (129^Lmnap.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 129^Lmnap.H222P mice showed significantly reduced body weight and reduced cardiac function earlier than in the C57^Lmnap.H222P mice. We also revealed that only 129^Lmnap.H222P mice developed heart arrhythmias. The 129^Lmnap.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.