Aberrant interaction between TEAD1 and Lamin A/C causes cardiomyopathy

Abstract

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