1. Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor.
- Author
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Ng, Kwong-Man, Mok, Pamela Y, Butler, Amy W, Ho, Jenny C Y, Choi, Shing-Wan, Lee, Yee-Ki, Lai, Wing-Hon, Au, Ka-Wing, Lau, Yee-Man, Wong, Lai-Yung, Esteban, Miguel A, Siu, Chung-Wah, Sham, Pak C, Colman, Alan, and Tse, Hung-Fat
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AUTOPHAGY , *VESICLES (Cytology) , *BACTERIAL autophagic vacuoles , *DNA methylation , *DNA - Abstract
Background: 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. [ABSTRACT FROM AUTHOR]- Published
- 2016
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