Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction
| Autor: | Naoki Yoshimura, Asami Takasaki, Kazuyoshi Saito, Neil E. Bowles, Fukiko Ichida, Nariaki Miyao, Sayaka Ozawa, Naoki Nishida, Hideyuki Nakaoka, Masafumi Takeda, Ce Wang, Michikazu Sekine, Yukiko Hata, Bo Chang, Keijiro Ibuki, Keiichi Hirono, Jun K Yamashita, Mako Okabe |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Sarcomeres Adolescent Heart Ventricles TPM1 030204 cardiovascular system & hematology Biology medicine.disease_cause Sarcomere Primary cardiomyopathy 03 medical and health sciences Young Adult 0302 clinical medicine Asian People Japan medicine Humans Calcium Signaling Child Genetics Mutation Heart development ACTC1 Infant Newborn Infant Prognosis Tropomyosin 030104 developmental biology Child Preschool Pediatrics Perinatology and Child Health Left ventricular noncompaction Female |
| Zdroj: | Pediatric research. 84(5) |
| ISSN: | 1530-0447 |
| Popis: | 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. 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. 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. |
| Databáze: | OpenAIRE |
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