Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor.
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.
['Ng|Kwong-Man|KM|', 'Mok|Pamela Y|PY|', 'Butler|Amy W|AW|', 'Ho|Jenny C Y|JC|', 'Choi|Shing-Wan|SW|', 'Lee|Yee-Ki|YK|', 'Lai|Wing-Hon|WH|', 'Au|Ka-Wing|KW|', 'Lau|Yee-Man|YM|', 'Wong|Lai-Yung|LY|', 'Esteban|Miguel A|MA|', 'Siu|Chung-Wah|CW|', 'Sham|Pak C|PC|', 'Colman|Alan|A|', 'Tse|Hung-Fat|HF|']
D000328:Adult D000483:Alleles D001343:Autophagy D001374:Azacitidine D002460:Cell Line D041321:Chromosomes, Human, X D005260:Female D052120:Glycogen Storage Disease Type IIb D006801:Humans D057026:Induced Pluripotent Stem Cells D052119:Lysosomal-Associated Membrane Protein 2 D008297:Male
autophagy X-linked vacuolar cardiomyopathy and myopathy glycogen storage disease type IIb