TEAD1 trapping by the Q353R–Lamin A/C causes dilated cardiomyopathy

• DOI: 10.1126/sciadv.ade7047
• Publication Date: 2023-04-14T17:58:17Z
• Authors: Shintaro Yamada; Toshiyuki Ko; Masamichi Ito; Tatsuro Sassa; Seitaro Nomura; Hiromichi Okuma; Mayuko Sato; Tsuyoshi Imasaki; Satoshi Kikkawa; Bo Zhang; Takanobu Yamada; Yuka Seki; Kanna Fujita; Manami Katoh; Masayuki Kubota; Satoshi Hatsuse; Mikako Katagiri; Hiromu Hayashi; Momoko Hamano; Norifumi Takeda; Hiroyuki Morita; Shuji Takada; Masashi Toyoda; Masanobu Uchiyama; Masashi Ikeuchi; Kiminori Toyooka; Akihiro Umezawa; Yoshihiro Yamanishi; Ryo Nitta; Hiroyuki Aburatani; Issei Komuro
• Keywords: LMNA; Nuclear lamina; Dilated Cardiomyopathy

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using (ATAC-seq), protein array, electron microscopy analysis, we show that insufficient structural maturation cardiomyocytes owing to trapping transcription factor TEA domain 1 (TEAD1) mutant A/C at membrane underlies pathogenesis Q353R -LMNA– related DCM. Inhibition Hippo pathway rescued dysregulation cardiac developmental genes TEAD1 cardiomyocytes. Single-cell RNA-seq tissues from patients with DCM mutation confirmed dysregulated expression target genes. Our results propose an intervention transcriptional as a potential treatment -related