Lamp2 cardiomyopathy: Consequences of impaired autophagy in the heart

Ronny Alcalai, Michael Arad*, Hiroko Wakimoto, Dor Yadin, Joshua Gorham, Libin Wang, Elia Burns, Barry J. Maron, William C. Roberts, Tetsuo Konno, David A. Conner, Antonio R. Perez-Atayde, Jon G. Seidman, Christine E. Seidman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Human mutations in the X-linked lysosome-associated membrane protein-2 (LAMP2) gene can cause a multi-system Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an in-frame LAMP2 gene exon 6 deletion mutation (denoted L2Δ6 ) causing human cardiomyopathy, into mouse LAMP2 gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in in-frame deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. METHODS AND RESULTS: Left ventricular tissues from L2Δ6 and wild-type mice had equivalent amounts of LAMP2 RNA, but a significantly lower level of LAMP2 protein. By 20 weeks 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-week-old L2Δ6 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 L2Δ6 hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis. CONCLUSIONS: 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.

Original languageEnglish
Article numbere018829
JournalJournal of the American Heart Association
Issue number17
StatePublished - 7 Sep 2021
Externally publishedYes


FundersFunder number
Machiah Foundation/Jewish Community Foundation
National Institutes of Health
Howard Hughes Medical Institute
National Heart, Lung, and Blood InstituteR01HL080494
National Heart, Lung, and Blood Institute
Chief Scientist Office
Ministry of Health, State of Israel


    • Autophagy
    • Calcium transients
    • Cardiomyopathy
    • Danon disease
    • Mouse model


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