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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References
Danon, M. J. et al. Lysosomal glycogen storage disease with normal acid maltase. Neurology 31, 51–57 (1981).
Muntoni, F. et al. Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments. Neuromusc. Disord. 4, 233–241 (1994).
Murakami, N. et al. Sarcolemmal indentation in cardiomyopathy with mental retardation and vacuolar myopathy. Neuromusc. Disord. 5, 149–155 (1995).
Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2 deficient mice. Nature 406, 902– 906 (2000).
Fukuda, M. Biogenesis of the lysosomal membrane. Subcell. Biochem. 22, 199–230 (1994).
Konecki, D. S., Foetisch, K., Zimmer, K. P., Schlotter, M. & Lichter-Konecki, U. An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochem. Biophys. Res. Commun. 215, 757–767 (1995).
Lewin, B. Genes VI (Oxford Univ. Press, Oxford, 1997).
Sutton, K. A. & Wilkinson, M. F. The rapidly evolving Pem homeobox gene and Agtr2, Ant2, and Lamp2 are closely linked in the proximal region of the mouse X chromosome. Genomics 45, 447–450 (1997).
Verloes, A. et al. Nosology of lysosomal glycogen storage diseases without in vitro acid maltase deficiency. Delineation of a neonatal form. Am. J. Med. Genet. 72, 135–142 (1997).
Morisawa, Y. et al. Lysosomal glycogen storage disease with normal acid maltase with early fatal outcome. J. Neurol. Sci. 160, 175–179 (1998).
Villanova, M. et al. X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers. Ann. Neurol. 37, 637–645 (1995).
Louboutin, J. P. et al. Elevated levels of complement components C5 and C9 and decreased antitrypsin activity in the serum of patients with X-linked vacuolated myopathy. Muscle Nerve 19, 1144– 1147 (1996).
Louboutin, J. P., Villanova, M., Lucas-Heron, B. & Fardeau, M. X-linked vacuolated myopathy: membrane attack complex deposition on muscle fiber membranes with calcium accumulation on sarcolemma. Ann. Neurol. 41, 117–120 ( 1997).
Villard, L. et al. Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28. Eur. J. Hum. Genet. 8, 125– 129 (2000).
Auranen, M. et al. X-linked vacuolar myopathies: two separate loci and refined genetic mapping. Ann. Neurol. 47, 666– 669 (2000).
Mattei, M. G., Matterson, J., Chen, J. W., Williams, M. A. & Fukuda, M. Two human lysosomal membrane glycoproteins, h-lamp-1 and h-lamp-2, are encoded by genes localized to chromosome 13q34 and chromosome Xq24-25, respectively. J. Biol. Chem. 265, 7548–7551 (1990).
Kannan, K. et al. Cell surface expression of lysosome-associated membrane protein-2 (lamp2) and CD63 as markers of in vivo platelet activation in malignancy. Eur. J. Haematol. 55, 145– 151 (1995).
Saitoh, O., Wang, W. C., Lotan, R. & Fukuda, M. Differential glycosylation and cell surface expression of lysosomal membrane glycoproteins in sublines of a human colon cancer exhibiting distinct metastatic potentials. J. Biol. Chem. 267, 5700–5711 (1992).
Cuervo, A. M. & Dice, J. F. Lysosomes, a meeting point of proteins, chaperones, and proteases. J. Mol. Med. 76, 6–12 (1998).
Town, M. et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nature Genet. 18, 319–324 (1998).
Verheijen, F. W. et al. A new gene, encoding an anion transporter, is mutated in sialic acid storage disease. Nature Genet. 23, 462–465 (1999).
Gahl, W. A., Schneider, J. A. & Aula, P. P. in The Metabolic and Molecular Bases of Inherited Disease (eds Schriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 3763–3797 (McGraw-Hill, New York, 1995).
Matsumoto, S. et al. Hepatic involvement in a case of lysosomal glycogen storage disease with normal acid maltase (translation). Rinsho Shinkeigaku 39, 717–721 ( 1999).
Itoh, M. et al. A patient with lysosomal glycogen storage disease with normal acid maltase (translation). No To Hattatsu 25, 459–464 (1993).
Katsumi, Y., Tokonami, F., Matsui, M., Aii, H. & Nonaka, I. A case of glycogen storage disease with normal acid maltase accompanied with the abnormal platelet function (translation). Rinsho Shinkeigaku 34, 827–831 ( 1994).
Katsumi, Y. et al. Cerebral oxygen and glucose metabolism in glycogen storage disease with normal acid maltase: case report. J. Neurol. Sci. 140, 46–52 ( 1996).
Dworzak, F. et al. Lysosomal glycogen storage with normal acid maltase: a familial study with successful heart transplant. Neuromusc. Disord. 4, 243–247 (1994).
Riggs, J. E. et al. Lysosomal glycogen storage disease without acid maltase deficiency. Neurology 33, 873–877 (1983).
Byrne, E. et al. Dominantly inherited cardioskeletal myopathy with lysosomal glycogen storage and normal acid maltase levels. Brain 109, 523–536 (1986).
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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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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DOI: https://doi.org/10.1038/35022604
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