Background Human mutations in the X-linked lysosome-associated membrane protein-2 (LAMP2) 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 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.