Abstract
Background
Left ventricular noncompaction (LVNC) is a primary cardiomyopathy with heterogeneous genetic origins. The aim of this study was to elucidate the role of sarcomere gene variants in the pathogenesis and prognosis of LVNC.
Methods and results
We screened 82 Japanese patients (0–35 years old), with a diagnosis of LVNC, for mutations in seven genes encoding sarcomere proteins, by direct DNA sequencing. We identified variants in a significant proportion of cases (27%), which were associated with poor prognosis (p = 0.012), particularly variants in TPM1, TNNC1, and ACTC1 (p = 0.012). To elucidate the pathological role, we developed and studied human-induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p.Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Microarray analysis indicated that the TPM1 mutation resulted in the down-regulation of the expression of numerous genes involved in heart development, and positive regulation of cellular process, especially the calcium signaling pathway.
Conclusions
Sarcomere genes are implicated as genetic triggers in the development of LVNC, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.
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Acknowledgements
We gratefully acknowledge W, Chung, L.J. Addnizio, and all Noncompaction study collaborators (Supplement S8). We are also grateful to the patients and families for their participation and to the referring clinicians for supporting the study. We thank Professor Yuichi Adachi for the steadfast counsel and guidance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (Research Project Number: 15K09685, 24591571, and 17591072) and by Japan Heart Foundation Research Grant on Dilated Cardiomyopathy to F.I.
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Takasaki, A., Hirono, K., Hata, Y. et al. Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction. Pediatr Res 84, 733–742 (2018). https://doi.org/10.1038/s41390-018-0162-1
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DOI: https://doi.org/10.1038/s41390-018-0162-1
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