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Article: Modeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells

TitleModeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells
Authors
KeywordsDilated cardiomyopathy
Lamin A/C cardiomyopathy
Nonsense mutation
PTC124
Translational read through
Issue Date2017
PublisherWiley Open Access. The Journal's web site is located at http://jaha.ahajournals.org/
Citation
Journal of the American Heart Association, 2017, v. 6 n. 8, article no. e005677, p. 1-36 How to Cite?
AbstractBackground: 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. PTC124 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 PTC124 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, PTC124 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 PTC124 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 PTC124 is codon selective. A premature stop codon UGA appeared to be most responsive to PTC124 treatment.
Persistent Identifierhttp://hdl.handle.net/10722/246561
ISSN
2019 Impact Factor: 4.605
2015 SCImago Journal Rankings: 2.484
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLee, YK-
dc.contributor.authorLau, YM-
dc.contributor.authorCai, Z-
dc.contributor.authorLai, WH-
dc.contributor.authorWong, LY-
dc.contributor.authorTse, HF-
dc.contributor.authorNg, KM-
dc.contributor.authorSiu, CW-
dc.date.accessioned2017-09-18T02:30:38Z-
dc.date.available2017-09-18T02:30:38Z-
dc.date.issued2017-
dc.identifier.citationJournal of the American Heart Association, 2017, v. 6 n. 8, article no. e005677, p. 1-36-
dc.identifier.issn2047-9980-
dc.identifier.urihttp://hdl.handle.net/10722/246561-
dc.description.abstractBackground: 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. PTC124 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 PTC124 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, PTC124 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 PTC124 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 PTC124 is codon selective. A premature stop codon UGA appeared to be most responsive to PTC124 treatment.-
dc.languageeng-
dc.publisherWiley Open Access. The Journal's web site is located at http://jaha.ahajournals.org/-
dc.relation.ispartofJournal of the American Heart Association-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectDilated cardiomyopathy-
dc.subjectLamin A/C cardiomyopathy-
dc.subjectNonsense mutation-
dc.subjectPTC124-
dc.subjectTranslational read through-
dc.titleModeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells-
dc.typeArticle-
dc.identifier.emailLee, YK: carol801@hku.hk-
dc.identifier.emailLau, YM: vymlau@hku.hk-
dc.identifier.emailCai, Z: caizj@HKUCC-COM.hku.hk-
dc.identifier.emailLai, WH: kwhlai@hku.hk-
dc.identifier.emailWong, LY: navywong@hkucc.hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.emailNg, KM: skykmng@hkucc.hku.hk-
dc.identifier.emailSiu, CW: cwdsiu@hkucc.hku.hk-
dc.identifier.authorityLee, YK=rp02636-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.authorityNg, KM=rp01670-
dc.identifier.authoritySiu, CW=rp00534-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1161/JAHA.117.005677-
dc.identifier.pmid28754655-
dc.identifier.pmcidPMC5586427-
dc.identifier.scopuseid_2-s2.0-85030668113-
dc.identifier.hkuros276947-
dc.identifier.volume6-
dc.identifier.issue8-
dc.identifier.spagearticle no. e005677, p. 1-
dc.identifier.epagearticle no. e005677, p. 36-
dc.identifier.isiWOS:000406948200011-
dc.publisher.placeUnited States-

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