title: HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy.
abstract: Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
authors: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu.
authors: John T
authors: JT
authors: Hinson
authors: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors: Anant
authors: A
authors: Chopra
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Navid
authors: N
authors: Nafissi
authors: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors: William J
authors: WJ
authors: Polacheck
authors: Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Craig C
authors: CC
authors: Benson
authors: Department of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56 D-44780, Bochum, Germany.
authors: Sandra
authors: S
authors: Swist
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Joshua
authors: J
authors: Gorham
authors: The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Luhan
authors: L
authors: Yang
authors: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Sebastian
authors: S
authors: Schafer
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Calvin C
authors: CC
authors: Sheng
authors: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: Alireza
authors: A
authors: Haghighi
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Jason
authors: J
authors: Homsy
authors: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
authors: Norbert
authors: N
authors: Hubner
authors: The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: George
authors: G
authors: Church
authors: National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease at Royal Brompton and Harefield National Health Service (NHS) Foundation Trust, Imperial College London, London, UK. National Heart Centre and Duke-National University, Singapore, Singapore.
authors: Stuart A
authors: SA
authors: Cook
authors: Department of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56 D-44780, Bochum, Germany.
authors: Wolfgang A
authors: WA
authors: Linke
authors: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors: Christopher S
authors: CS
authors: Chen
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: J G
authors: JG
authors: Seidman
authors: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu.
authors: Christine E
authors: CE
authors: Seidman
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D064211:Connectin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D006339:Heart Rate; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D050505:Mutant Proteins / Q000737:chemistry / Q000502:physiology; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000502:physiology* / Q000648:ultrastructure; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D000318:Adrenergic beta-Agonists; D064211:Connectin; D050505:Mutant Proteins; C577285:TTN protein, human; D012313:RNA; D007545:Isoproterenol