Trends in Molecular Medicine
ReviewDisease model: LAMP-2 enlightens Danon disease
Section snippets
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
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2023, Biochemical and Biophysical Research CommunicationsClinical features of Danon disease and insights gained from LAMP-2 deficiency models
2023, Trends in Cardiovascular MedicineCitation Excerpt :First, many heterozygous female DD patients can have clinical manifestations as the age increases, whereas heterozygous female mice exhibit no abnormalities. In addition, human cardiomyocytes exhibit a greater degree of vacuolation than mice cardiomyocytes [47]. Although cardiac abnormality is the leading death reason in human DD patients, the cardiac phenotype in these mice is milder than in humans.
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2020, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :Furthermore, autophagic flux was impaired in Danon iPSC-CMs [53]. LAMP-2-deficient mice exhibit increased mortality, cardiac hypertrophy and reduced cardiac contractile function (Table 3; [22,49,50]). Similar to Danon patients, accumulation of autophagic vacuoles has been observed in the heart and skeletal muscle of LAMP-2-deficient mice [22,49,50].