Open AccessModeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells
Author(s) -
Lee YeeKi,
Lau YeeMan,
Cai ZhuJun,
Lai WingHon,
Wong LaiYung,
Tse HungFat,
Ng KwongMan,
Siu ChungWah
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.005677
Subject(s) - lmna , induced pluripotent stem cell , lamin , cardiomyopathy , medicine , cancer research , nonsense mutation , microbiology and biotechnology , genetics , mutation , biology , gene , heart failure , embryonic stem cell , missense mutation
Background Precision medicine is an emerging approach to disease treatment and prevention that takes into account individual variability in the environment, lifestyle, and genetic makeup of patients. Patient‐specific human induced pluripotent stem cells hold promise to transform precision medicine into real‐life clinical practice. Lamin A/C ( LMNA )‐related cardiomyopathy is the most common inherited cardiomyopathy in which a substantial proportion of mutations in the LMNA gene are of nonsense mutation. PTC 124 induces translational read‐through over the premature stop codon and restores production of the full‐length proteins from the affected genes. In this study we generated human induced pluripotent stem cells‐derived cardiomyocytes from patients who harbored different LMNA mutations (nonsense and frameshift) to evaluate the potential therapeutic effects of PTC 124 in LMNA ‐related cardiomyopathy. Methods and Results We generated human induced pluripotent stem cells lines from 3 patients who carried distinctive mutations (R225X, Q354X, and T518fs) in the LMNA gene. The cardiomyocytes derived from these human induced pluripotent stem cells lines reproduced the pathophysiological hallmarks of LMNA ‐related cardiomyopathy. Interestingly, PTC 124 treatment increased the production of full‐length LMNA proteins in only the R225X mutant, not in other mutations. Functional evaluation experiments on the R225X mutant further demonstrated that PTC 124 treatment not only reduced nuclear blebbing and electrical stress‐induced apoptosis but also improved the excitation‐contraction coupling of the affected cardiomyocytes. Conclusions Using cardiomyocytes derived from human induced pluripotent stem cells carrying different LMNA mutations, we demonstrated that the effect of PTC 124 is codon selective. A premature stop codon UGA appeared to be most responsive to PTC 124 treatment.