Review
Disease model: LAMP-2 enlightens Danon disease

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Abstract

Danon disease (‘lysosomal glycogen storage disease with normal acid maltase’) is characterized by a cardiomyopathy, myopathy and variable mental retardation. Mutations in the coding sequence of the lysosomal-associated membrane protein 2 (LAMP-2) were shown to cause a LAMP-2 deficiency in patients with Danon disease. LAMP-2 deficient mice manifest a similar vacuolar cardioskeletal myopathy. In addition to the patient reports LAMP-2 deficiency in mice causes pancreatic, hepatocytic, endothelial and leucocyte vacuolation. LAMP-2 deficient mice represent a valuable animal model of Danon disease. They will further be used to study the exact role of LAMP-2 in autophagy and to analyse the consequences of an impaired autophagic pathway in various tissues.

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A mouse model for Danon disease

In many aspects, LAMP-2-deficient mice 7 represent a valuable animal model of Danon disease (Table 1). LAMP-2-deficient mice are fertile and viable, but have a low body weight. Approximately half of LAMP-2-deficient mice die between three and six weeks of birth. They are characterized by haemorrhagic infarction of the small intestine, pancreatic lesions and altered morphology of spleen and thymus. Excessive accumulations of autophagosomes in liver, kidney, pancreas, heart and skeletal muscle

Autophagy in skeletal and heart muscle

As with the human disease, LAMP-2-deficient mice have autophagosomal alterations in heart and skeletal muscle (Fig. 1). Accumulation of autophagosomes is more pronounced in skeletal muscle (Fig. 1b) and in heart muscle (Fig. 1a) where the number increases with age. In mice, as in patients, skeletal muscle pathology is more severe in proximal muscles, such as the M. sternomastoideus and biceps, where fibre degeneration is also observed occasionally. Some vacuoles in these muscle cells contain

Function of LAMP-2 in autophagy

In addition to providing a relevant model for Danon disease, LAMP-2-deficient mice are useful to study the role of this lysosomal membrane protein in autophagy. In hepatocytes in culture, a lack of LAMP-2 causes impaired degradation of autophagocytosed proteins 7. LAMP-2 might be involved in fusion of autophagosomes with the endosomal or lysosomal compartments 9. To our knowledge, LAMP-2-deficient mice also present the first genetically defined mammalian model to study the consequences of an

Conclusions

Mice deficient in LAMP-2 have pathological features of Danon disease in humans, although some clinical traits, such as mental retardation, are difficult to evaluate in mouse models. Furthermore, some aspects of the mouse pathology, such as pancreatic, endothelial and leukocyte vacuolation are not reported in patients with Danon disease (although it is possible that these abnormalities will be found in human cases). Because some aspects of LAMP-2-deficient mice resemble the clinical

References (9)

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