Why the study?
Mutations in LEM domain-containing protein 2 (LEMD2) cause severe cardiomyopathy in humans, but the roles of LEMD2 in the heart and the pathological mechanisms responsible for its disease association are unknown.
Does cardiomyocyte-specific Lemd2 gene therapy rescue cardiac function in mice with LEMD2 mutation-induced cardiomyopathy?
Does cardiomyocyte-specific Lemd2 gene therapy rescue cardiac function in mice with LEMD2 mutation-induced cardiomyopathy?
LEMD2 is essential for genome stability and cardiac function, and AAV-mediated gene therapy can rescue cardiac function in a preclinical model of LEMD2-associated cardiomyopathy.
Lemd2 loss drives DNA damage-dependent cardiomyopathy in mice; leaves open whether pathway targeting merits human trials.
Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, that primarily affect the heart and skeletal muscle. A mutation in the NEP LEM domain-containing protein 2 (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. We generated knockin (KI) mice carrying the human c.T38>G Lemd2 mutation, which causes a missense amino acid exchange (p.L13>R) in the LEM domain of the protein. These mice represent a preclinical model that phenocopies the human disease, as they developed severe dilated cardiomyopathy and cardiac fibrosis leading to premature death. At the cellular level, KI/KI 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. Cardiomyocytes lacking Lemd2 displayed nuclear envelope deformations and extensive DNA damage and apoptosis linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus rescued cardiac function in KI/KI mice. Together, our results reveal the essentiality of LEMD2 for genome stability and cardiac function and unveil its mechanistic association with human disease.
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Caravia et al. (2022) studied this question.
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