Abstract
Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplantation. A portion of familial DCM is due to mutations in the LMNA gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognosis. To get better insights into pathobiology behind this disease, we focused on modeling LMNA-related DCM using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Primary skin fibroblasts from DCM patients carrying the most prevalent Finnish founder mutation (p.S143P) in LMNA were reprogrammed into hiPSCs and further differentiated into cardiomyocytes (CMs). The cellular structure, functionality as well as gene and protein expression were assessed in detail. While mutant hiPSC-CMs presented virtually normal sarcomere structure under normoxia, dramatic sarcomere damage and an increased sensitivity to cellular stress was observed after hypoxia. A detailed electrophysiological evaluation revealed bradyarrhythmia and increased occurrence of arrhythmias in mutant hiPSC-CMs on β-adrenergic stimulation. Mutant hiPSC-CMs also showed increased sensitivity to hypoxia on microelectrode array and altered Ca2+ dynamics. Taken together, p.S143P hiPSC-CM model mimics hallmarks of LMNA-related DCM and provides a useful tool to study the underlying cellular mechanisms of accelerated cardiac degeneration in this disease.
Highlights
Dilated cardiomyopathy (DCM) is a cardiac disorder characterized by weakening of the heart muscle due to a progressive loss of functional cardiomyocytes, dilation of cardiac ventricles, reduced cardiac output and arrhythmias [1]
Over 500 mutations identified in the LMNA gene cause an exceptional variety of diseases commonly called laminopathies
We have previously shown that p.S143P mutation increases lamin A/C nucleoplasmicity, mobility and tendency to form intranuclear aggregates in patient fibroblasts and further activates unfolded protein response (UPR) [25]
Summary
Dilated cardiomyopathy (DCM) is a cardiac disorder characterized by weakening of the heart muscle due to a progressive loss of functional cardiomyocytes, dilation of cardiac ventricles, reduced cardiac output and arrhythmias [1]. Mutations in more than 30 different genes have been linked to the genetic form of DCM and the second most commonly mutated gene is LMNA, encoding nuclear lamin A and C proteins [3,4,5]. Lamins play an essential role in determining nuclear size, shape, stiffness and they have been implicated in cell cycle progression, chromatin organization and DNA damage response [6]. A-type lamins, primarily lamin A and C, are derived through alternative splicing of the LMNA gene while. B-type lamins (lamin B1 and B2) are encoded by two distinct genes, LMNB1 and LMNB2, respectively. Over 500 mutations identified in the LMNA gene (http://www.umd.be/LMNA/) cause an exceptional variety of diseases commonly called laminopathies. In addition to DCM, these include e.g., muscular dystrophies, lipodystrophies, peripheral neuropathy and premature aging (progeria) [7], many of which exhibit some features of cardiac disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
