LAMP-2 deficiency in mice leads to increased mortality and accumulation of autophagic vacuoles in multiple tissues, including the heart, liver, and pancreas. The study shows that LAMP-2 is essential for autophagy, as its absence impairs the degradation of long-lived proteins in hepatocytes and causes severe cardiac dysfunction. These findings are supported by the observation that human LAMP-2 deficiency, causing Danon disease, is associated with similar autophagic vacuole accumulation in skeletal and cardiac muscle. The study also demonstrates that LAMP-2 is required for the maturation of autophagic vacuoles into degradative compartments, suggesting a role in the fusion of autophagic vacuoles with endosomes/lysosomes. LAMP-2-deficient mice exhibit reduced contractile function and increased heart weight, consistent with the clinical features of Danon disease. The study highlights the critical role of LAMP-2 in autophagy and its potential as a therapeutic target for diseases involving autophagic dysfunction. The research also identifies mutations in the LAMP-2 gene in patients with Danon disease, confirming its genetic basis. These findings provide important insights into the pathogenesis of Danon disease and the role of LAMP-2 in autophagy.LAMP-2 deficiency in mice leads to increased mortality and accumulation of autophagic vacuoles in multiple tissues, including the heart, liver, and pancreas. The study shows that LAMP-2 is essential for autophagy, as its absence impairs the degradation of long-lived proteins in hepatocytes and causes severe cardiac dysfunction. These findings are supported by the observation that human LAMP-2 deficiency, causing Danon disease, is associated with similar autophagic vacuole accumulation in skeletal and cardiac muscle. The study also demonstrates that LAMP-2 is required for the maturation of autophagic vacuoles into degradative compartments, suggesting a role in the fusion of autophagic vacuoles with endosomes/lysosomes. LAMP-2-deficient mice exhibit reduced contractile function and increased heart weight, consistent with the clinical features of Danon disease. The study highlights the critical role of LAMP-2 in autophagy and its potential as a therapeutic target for diseases involving autophagic dysfunction. The research also identifies mutations in the LAMP-2 gene in patients with Danon disease, confirming its genetic basis. These findings provide important insights into the pathogenesis of Danon disease and the role of LAMP-2 in autophagy.