Asami Takasaki1, Keiichi Hirono1, Yukiko Hata2, Ce Wang1,3, Masafumi Takeda4, Jun K Yamashita4, Bo Chang1, Hideyuki Nakaoka1, Mako Okabe1, Nariaki Miyao1, Kazuyoshi Saito1, Keijiro Ibuki1, Sayaka Ozawa1, Michikazu Sekine5, Naoki Yoshimura6, Naoki Nishida2, Neil E Bowles7, Fukiko Ichida8. 1. Department of Pediatrics, University of Toyama, Toyama, Japan. 2. Department of Legal Medicine, University of Toyama, Toyama, Japan. 3. Department of Pediatrics (Cardiology), Shengjing Hospital of China Medical University, Shenyang, China. 4. Department of Stem Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. 5. Department of Epidemiology and Health Policy, University of Toyama, Toyama, Japan. 6. Department of Thoracic and Cardiovascular Surgery, University of Toyama, Toyama, Japan. 7. Department of Pediatrics (Cardiology), University of Utah, Salt Lake City, UT, USA. 8. Department of Pediatrics, University of Toyama, Toyama, Japan. fkichida@ctg.u-toyama.ac.jp.
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.
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.
Authors: Tyler R Reinoso; Maicon Landim-Vieira; Yun Shi; Jamie R Johnston; P Bryant Chase; Michelle S Parvatiyar; Andrew P Landstrom; Jose R Pinto; Hanna J Tadros Journal: J Muscle Res Cell Motil Date: 2020-11-11 Impact factor: 3.352