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Article: Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor

TitleAmelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor
Authors
KeywordsAutophagy
X-linked vacuolar cardiomyopathy and myopathy
Glycogen storage disease type IIb
Issue Date2016
PublisherAmerican Heart Association. The Journal's web site is located at http://circ.ahajournals.org
Citation
Circulation, 2016, v. 134 n. 18, p. 1373-1389 How to Cite?
AbstractBackground: Danon disease is an X-linked disorder that leads to fatal cardiomyopathy caused by a deficiency in lysosome-associated membrane protein-2 (LAMP2). In female patients, a later onset and less severe clinical phenotype have been attributed to the random inactivation of the X chromosome carrying the mutant diseased allele. We generated a patient-specific induced pluripotent stem cell (iPSCs)–based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor. Methods: Using whole-exome sequencing, we identified a nonsense mutation (c.520C>T, exon 4) of the LAMP2 gene in a family with Danon disease. We generated iPSC lines from somatic cells derived from the affected mother and her 2 sons, and we then differentiated them into cardiomyocytes (iPSC-CMs) for modeling the histological and functional signatures, including autophagy failure of Danon disease. Results: Our iPSC-CM platform provides evidence that random inactivation of the wild-type and mutant LAMP2 alleles on the X chromosome is responsible for the unusual phenotype in female patients with Danon disease. In vitro, iPSC-CMs from these patients reproduced the histological features and autophagy failure of Danon disease. Administration of the DNA demethylating agent 5-aza-2’-deoxycytidine reactivated the silent LAMP2 allele in iPSCs and iPSC-CMs in female patients with Danon disease and ameliorated their autophagy failure, supporting the application of a patient-specific iPSC platform for disease modeling and drug screening. Conclusions: Our iPSC-CM platform provides novel mechanistic and therapeutic insights into the contribution of random X chromosome inactivation to disease phenotype in X-linked Danon disease.
Persistent Identifierhttp://hdl.handle.net/10722/244399
ISSN
2017 Impact Factor: 18.881
2015 SCImago Journal Rankings: 7.853
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNg, KM-
dc.contributor.authorMok, PY-
dc.contributor.authorButler, AW-
dc.contributor.authorHo, JC-
dc.contributor.authorChoi, SW-
dc.contributor.authorLee, YK-
dc.contributor.authorLai, KWH-
dc.contributor.authorAu, KW-
dc.contributor.authorLau, VYM-
dc.contributor.authorWong, LY-
dc.contributor.authorEsteban, MA-
dc.contributor.authorSiu, DCW-
dc.contributor.authorSham, PC-
dc.contributor.authorColman, A-
dc.contributor.authorTse, HF-
dc.date.accessioned2017-09-18T01:51:45Z-
dc.date.available2017-09-18T01:51:45Z-
dc.date.issued2016-
dc.identifier.citationCirculation, 2016, v. 134 n. 18, p. 1373-1389-
dc.identifier.issn0009-7322-
dc.identifier.urihttp://hdl.handle.net/10722/244399-
dc.description.abstractBackground: Danon disease is an X-linked disorder that leads to fatal cardiomyopathy caused by a deficiency in lysosome-associated membrane protein-2 (LAMP2). In female patients, a later onset and less severe clinical phenotype have been attributed to the random inactivation of the X chromosome carrying the mutant diseased allele. We generated a patient-specific induced pluripotent stem cell (iPSCs)–based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor. Methods: Using whole-exome sequencing, we identified a nonsense mutation (c.520C>T, exon 4) of the LAMP2 gene in a family with Danon disease. We generated iPSC lines from somatic cells derived from the affected mother and her 2 sons, and we then differentiated them into cardiomyocytes (iPSC-CMs) for modeling the histological and functional signatures, including autophagy failure of Danon disease. Results: Our iPSC-CM platform provides evidence that random inactivation of the wild-type and mutant LAMP2 alleles on the X chromosome is responsible for the unusual phenotype in female patients with Danon disease. In vitro, iPSC-CMs from these patients reproduced the histological features and autophagy failure of Danon disease. Administration of the DNA demethylating agent 5-aza-2’-deoxycytidine reactivated the silent LAMP2 allele in iPSCs and iPSC-CMs in female patients with Danon disease and ameliorated their autophagy failure, supporting the application of a patient-specific iPSC platform for disease modeling and drug screening. Conclusions: Our iPSC-CM platform provides novel mechanistic and therapeutic insights into the contribution of random X chromosome inactivation to disease phenotype in X-linked Danon disease.-
dc.languageeng-
dc.publisherAmerican Heart Association. The Journal's web site is located at http://circ.ahajournals.org-
dc.relation.ispartofCirculation-
dc.subjectAutophagy-
dc.subjectX-linked vacuolar cardiomyopathy and myopathy-
dc.subjectGlycogen storage disease type IIb-
dc.titleAmelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor-
dc.typeArticle-
dc.identifier.emailNg, KM: skykmng@hkucc.hku.hk-
dc.identifier.emailLee, YK: carol801@hku.hk-
dc.identifier.emailLai, KWH: kwhlai@hku.hk-
dc.identifier.emailAu, KW: aukawing@hku.hk-
dc.identifier.emailLau, VYM: vymlau@hku.hk-
dc.identifier.emailWong, LY: navywong@hkucc.hku.hk-
dc.identifier.emailSiu, DCW: cwdsiu@hkucc.hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.authorityNg, KM=rp01670-
dc.identifier.authoritySiu, DCW=rp00534-
dc.identifier.authoritySham, PC=rp00459-
dc.identifier.authorityTse, HF=rp00428-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1161/CIRCULATIONAHA.115.019847-
dc.identifier.pmid27678261-
dc.identifier.scopuseid_2-s2.0-84991467272-
dc.identifier.hkuros277688-
dc.identifier.volume134-
dc.identifier.issue18-
dc.identifier.spage1373-
dc.identifier.epage1389-
dc.identifier.isiWOS:000387348400020-
dc.publisher.placeUnited States-

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