Cardiac-specific inactivation of effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes.

A variant in the locus has been correlated with QRS duration in an electrocardiogram genome-wide association study, and the deletion of has been implicated as a causal factor of the dilated cardiomyopathy that is linked to 1p36 deletion syndrome. We aimed to determine how a null mutation of affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay. -null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR, -null hearts upregulated extracellular matrix-related genes (, ) and α-smooth muscle actin (), a myofibroblast marker. Moreover, TGF-β signaling was activated in -null hearts, as evidenced by increased transcript levels and phosphorylated Smad2. However, the inhibition of TGF-β receptor did not reverse the aberrations in conduction in cardiac-specific knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis, -null hearts experienced dysregulated expression of ion channel genes, including , , , and . Mice with -null hearts develop abnormalities in cardiac conduction and cardiomyopathy-associated phenotypes, including fibrosis and cellular hypertrophy. Further, the RNA-seq findings suggest that impairments in ion homeostasis (Ca, K, and Na) may at least partially underlie the abnormal conduction in cardiac-specific knockout mice. This is the first study that describes aberrant cardiac function and cardiomyopathy-associated phenotypes in an appropriate murine genetic model with cardiomyocyte-specific -null mutation. It is noteworthy that the correlation of with QRS duration is replicated in a murine animal model and the potential underlying mechanism may be the impairment of ion homeostasis.