GSE194218
Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy
Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, which primarily affect the heart and skeletal muscle. A mutation in the NEP LEMD2 causes severe cardiomyopathy in humans. However, the roles of LEMD2 in the heart and the pathological mechanisms responsible for its association with cardiac disease are unknown. To explore the mechanistic basis of this pathology, we generated mice carrying the human c.T38>G LEMD2 mutation. These mice phenocopied the human disease and developed severe dilated cardiomyopathy with extensive cardiac fibrosis leading to premature death. At the cellular level, LEMD2 mutant cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of LEMD2 also died shortly after birth due to heart abnormalities. LEMD2 mutant mice displayed aberrant cardiac gene expression and extensive DNA damage. The development of cardiac disease in both mouse models is linked to p53 activation. Together, our results reveal the essentiality of the nuclear envelope protein LEMD2 for genome stability and normal cardiac function. Overall design: Adult and P1 hearts; different genotypes.