{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:46:18Z","timestamp":1789145178063,"version":"build-2803163510"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>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)\u2013based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Using whole-exome sequencing, we identified a nonsense mutation (c.520C&gt;T, exon 4) of the\n              <jats:italic>LAMP2<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Our iPSC-CM platform provides evidence that random inactivation of the wild-type and mutant\n              <jats:italic>LAMP2<\/jats:italic>\n              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\u2019-deoxycytidine reactivated the silent\n              <jats:italic>LAMP2<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.115.019847","type":"journal-article","created":{"date-parts":[[2016,9,28]],"date-time":"2016-09-28T02:18:56Z","timestamp":1475029136000},"page":"1373-1389","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor"],"prefix":"10.1161","volume":"134","author":[{"given":"Kwong-Man","family":"Ng","sequence":"first","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela Y.","family":"Mok","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy W.","family":"Butler","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny C.Y.","family":"Ho","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shing-Wan","family":"Choi","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee-Ki","family":"Lee","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing-Hon","family":"Lai","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka-Wing","family":"Au","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee-Man","family":"Lau","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai-Yung","family":"Wong","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Esteban","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Wah","family":"Siu","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak C.","family":"Sham","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Colman","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary Hospital, Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine (K.-M.N, C.W.-S., H.-F.T.), Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (M.A.E., H.-F.T.), Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine (P.C.S.),..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Fat","family":"Tse","sequence":"additional","affiliation":[{"name":"From Cardiology Division, Department of Medicine (K.-M.N., J.C.Y.H., Y.-K.L., W.-H.L., K.-W.A., Y.-M.L., L.-Y.W., C.-W.S., H.-F.T.) and Department of Psychiatry (A.W.B., S.-W.C., P.C.S., A.C.), Queen Mary 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