{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T15:45:58Z","timestamp":1793202358192,"version":"4.5.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,9,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Human mutations in the X\u2010linked lysosome\u2010associated membrane protein\u20102 (\n              <jats:italic>LAMP2<\/jats:italic>\n              ) gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an\n              <jats:italic>in\u2010frame LAMP2 gene exon 6 deletion<\/jats:italic>\n              mutation (denoted L2\n              <jats:sup>\u03946<\/jats:sup>\n              ) causing human cardiomyopathy, into mouse\n              <jats:italic>LAMP2<\/jats:italic>\n              gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in\n              <jats:italic>in\u2010frame<\/jats:italic>\n              deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Left ventricular tissues from L2\n              <jats:sup>\u03946<\/jats:sup>\n              and wild\u2010type mice had equivalent amounts of\n              <jats:italic>LAMP2<\/jats:italic>\n              RNA, but a significantly lower level of LAMP2 protein. By 20\u00a0weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40\u2010week\u2010old L2\n              <jats:sup>\u03946<\/jats:sup>\n              mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression analyses of L2\n              <jats:sup>\u03946<\/jats:sup>\n              hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">We suggest that impaired autophagy results in cardiac hypertrophy and profound transcriptional reactions that impacted metabolism, calcium homeostasis, and cell survival. These responses define the molecular pathways that underlie the pathology and aberrant electrophysiology in cardiomyopathy of Danon disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.018829","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T09:10:49Z","timestamp":1630141849000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":41,"title":["<i>LAMP2<\/i>\n            Cardiomyopathy: Consequences of Impaired Autophagy in the Heart"],"prefix":"10.1161","volume":"10","author":[{"given":"Ronny","family":"Alcalai","sequence":"first","affiliation":[{"name":"Heart InstituteHadassah Hebrew University Medical Center Jerusalem Israel"},{"name":"Department of Genetics Harvard Medical School Boston 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