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Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE194218 | GEO | 2022/10/13

REPOSITORIES: GEO

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Lem2 is essential for cardiac development by maintaining nuclear integrity

Project description:Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.

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Interplay of stress responses underlying the development of LMNA cardiomyopathy

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2022-10-11 | GSE185620 | GEO

Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy [ChIP-seq]

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2023-06-08 | GSE232046 | GEO

Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy [snRNA-seq]

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Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy [RNA-seq]

2023-06-08 | GSE232047 | GEO

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2021-11-03 | PXD024594 | Pride

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Gene expression profiling on mouse models of dilated cardiomyopathy

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