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Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease)

Abstract

“Lysosomal glycogen storage disease with normal acid maltase”, which was originally described by Danon et al.1, is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes2,3. Here we report ten unrelated patients, including one of the patients from the original case report1, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease4. To our knowledge this is the first example of human cardiopathy–myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.

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Figure 1: Representative electropherograms of the LAMP-2 gene mutations.
Figure 2: Representation of the mutant LAMP-2b.
Figure 3: Western blot analysis.
Figure 4: Immunohistochemistry.

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Acknowledgements

We thank patients and their families for their cooperation. We thank K. Murayama, F. Igarashi, S. Tadesse for technical assistance; E. A. Schon, L. Salviati, F. Pallotti, A. Spinazzola, J. Ojaimi, S. Tsujino, N. Minami, M. Ikezawa, Y. Goto, H. Sugita for helpful discussion; and H. Kato, T. Ohi, M. Itoh, Y. Katsumi, T. Wada, X. Dennett, and A. P. Hays for providing samples. M.H. is supported by grants from the National Institutes of Health and the Muscular Dystrophy Association.

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Correspondence to Ichizo Nishino.

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Nishino, I., Fu, J., Tanji, K. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000). https://doi.org/10.1038/35022604

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