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. Adult and P1 hearts; different genotypes核被膜蛋白（nuclear envelope proteins, NEPs）的突变会引发毁灭性的遗传疾病，这类疾病被命名为核被膜病（envelopathies），主要累及心脏与骨骼肌。其中，核被膜蛋白LEMD2的突变可导致人类罹患重症心肌病，但目前LEMD2在心脏中的具体作用，以及其与心脏疾病相关的病理机制仍未阐明。为探究该病理过程的分子机制，我们构建了携带人类c.T38>G LEMD2突变的小鼠模型。该小鼠模型重现了人类疾病表型，并发展出伴有广泛心肌纤维化的重症扩张型心肌病，最终导致过早死亡。在细胞水平上，携带LEMD2突变的心肌细胞出现了与核被膜相关的转录沉默型异染色质结构紊乱。此外，心脏特异性敲除LEMD2的小鼠同样因心脏异常在出生后短期内死亡。LEMD2突变小鼠表现出异常的心脏基因表达谱与广泛的DNA损伤。两种小鼠模型中心脏疾病的发生均与p53激活相关。综上，本研究结果揭示了核被膜蛋白LEMD2对于维持基因组稳定性与心脏正常功能的必要性。本数据集涵盖成年小鼠及出生后1天（Postnatal day 1, P1）的心脏组织，包含不同基因型样本。