Abstract P1106: 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. As a consequence, there is no specific therapy for this cardiomyopathy. To explore the basis of this pathology, we generated mice carrying the human c.T38>G Lemd2 mutation. These mice represent a new preclinical model that 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. Both LEMD2 mutant models displayed aberrant cardiac gene expression and extensive DNA damage linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus significantly rescued cardiac function in the c.T38>G mice. Together, our results reveal the essentiality of the nuclear envelope protein LEMD2 for genome stability and cardiac function and unveil its mechanistic association with human disease.