Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction

Asami Takasaki, Keiichi Hirono, Yukiko Hata, Ce Wang, Masafumi Takeda, Jun K. Yamashita, Bo Chang, Hideyuki Nakaoka, Mako Okabe, Nariaki Miyao, Kazuyoshi Saito, Keijiro Ibuki, Sayaka Ozawa, Michikazu Sekine, Naoki Yoshimura, Naoki Nishida, Neil E. Bowles, Fukiko Ichida

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)733-742
Number of pages10
JournalPediatric Research
Volume84
Issue number5
DOIs
Publication statusPublished - 01-11-2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

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