LEMD2, the gene encoding LEM domain-containing protein 2, is an inner nuclear membrane protein. It plays crucial roles in maintaining nuclear envelope integrity, chromatin organization, and is involved in DNA damage response pathways. The protein contains a Lap2/Emerin/Man1 (LEM)-domain which is important for its interactions with other proteins [1,2].

Knock-in mice carrying the human c.T38>G Lemd2 mutation (p.L13>R in the LEM domain) developed severe dilated cardiomyopathy, cardiac fibrosis, and premature death [2]. These mice recapitulated human disease phenotypes, such as ventricular arrhythmias and conduction disease [1]. In knock-in cardiomyocytes, there were increased nuclear membrane invaginations, decreased nuclear circularity, increased DNA damage, and premature senescence [1]. The p.L13R mutation disrupted the interaction between mutant LEMD2 and BAF, impairing the nuclear envelope rupture repair process [1]. Additionally, in mutant HeLa-cells under increased mechanical stress, there was impaired nuclear envelope rupture repair, cytoplasmic leakage of the DNA repair factor KU80, increased DNA damage, and recruitment of cGAS to the nuclear membrane and micronuclei [1].

In conclusion, LEMD2 is essential for genome stability and cardiac function. Studies using Lemd2 knock-in mouse models have revealed its role in maintaining nuclear architecture and DNA integrity, and its disruption is associated with the development of cardiomyopathy. Understanding LEMD2's function provides insights into the pathogenesis of related heart diseases and may offer potential targets for treatment.