The pathology of severe dilated cardiomyopathy elucidated, and its new therapeutic target identified

April 17, 2023

Multifaceted analysis of model mice and iPS cell-derived cardiomyocytes

The research group, composed of researchers from the University of Tokyo, the RIKEN CSRS, Tokyo Medical and Dental University, Kobe University, and the National Center for Child Health and Development, established disease model mice and disease-specific iPS cell-derived cardiomyocytes that reproduce a genetic mutation (LMNA Q353R) identified through genetic analysis of a family lineage of patients with severe dilated cardiomyopathy (DCM). They then analyzed them using various technologies, including electron microscopy with high-pressure freezing, single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and protein array analysis. With society aging, the number of patients with chronic heart failure keeps rising in Japan and other advanced countries. It is known that the therapeutic outcomes of this disorder are as poor as or poorer than those of malignant tumors. It is also known that severe DCM is one of the underlying diseases of chronic heart failure, and mutations in the Lamin A gene (LMNA), one of the major components of the nuclear lamina, cause particularly severe DCM. However, its underlying pathogenic mechanism has not been elucidated. The research group revealed that mutant Lamin molecules impair the function of transcription factor TEA domain transcription factor 1 (TEAD1), which is required to mature cardiomyocytes.

Original article

Science Advances doi:10.1126/sciadv.ade7047

S. Yamada, T. Ko, M. Ito, T. Sassa, S. Nomura, H. Okuma, M. Sato, T. Imasaki, S. Kikkawa, B. Zhang, T. Yamada, Y. Seki, K. Fujita, M. Katoh, M. Kubota, S. Hatsuse, M. Katagiri, H. Hayashi, M. Hamano, N. Takeda, H. Morita, S. Takada, M. Toyoda, M. Uchiyama, M. Ikeuchi, K. Toyooka, A. Umezawa, Y. Yamanishi, R. Nitta, H. Aburatani, I. Komuro,

"TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy".

Contact

Kiminori Toyooka; Senior Technical Scientist
Mayuko Sato; Technical Scientist
Mass Spectrometry and Microscopy Unit