Aberrant interaction between TEAD1 and Lamin A/C causes cardiomyopathy

Abstract Background Mutations in the LMNA gene encoding Lamin A/C, a major component of nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM). DCM patients with mutations have particularly severe clinical courses such as heart transplantation and death due to failure. However, underlying mechanisms LMNA-induced remains elusive. Methods results We identified Q353R mutation family generated heterozygous knock-in mice, which showed sarcomere dysplasia perinatal lethality. Integrative single-cell analyses fetal murine hearts patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSCMs) revealed that transcriptional regulation cardiomyocyte maturation/development genes governed by TEAD1 was impaired mutant cardiomyocytes. Protein array immunostaining uncovered increased binding A/C protein abnormal localization at periphery. Furthermore, TT-10, Hippo pathway inhibitor, rescued dysregulation cardiac developmental Single-cell RNA-seq tissues from confirmed dysregulated expression its target genes. These demonstrated interaction between impairs structural maturation suggests Q353R-related can be treated through intervention pathway. Conclusion trapped membrane perturbs DCM. Funding Acknowledgement Type funding sources: None.