Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor. Issue 18 (1st November 2016)

• Record Type: Journal Article
• Authors: 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; Tse, Hung-Fat
• Is Part Of: Circulation. Volume 134:Issue 18(2016)
• Publication Date: 2016-11-01
• Subjects: autophagy -- glycogen storage disease type IIb -- X-linked vacuolar cardiomyopathy and myopathy; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.115.019847
• Languages: English
• ISSNs: 0009-7322

Abstract

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 : Supplemental Digital Content is available in the text.