Abstract
Danon disease is an X-linked disorder clinically characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Cardiomyopathy is a severe and life-threatening problem, for which cardiac transplantation is the only therapeutic option. The most striking finding in muscle biopsy samples is small basophilic granules scattered in myofibers, which are in fact small autophagic vacuoles surrounded by membranes with sarcolemmal features characterized by the recruitment of sarcolemmal proteins and acetylcholine esterase and by the presence of basal lamina on its luminal side. The mechanism underlying the formation of these autophagic vacuoles with unique sarcolemmal features (AVSF) still remains a mystery and its origin is unknown. In heart, cardiomyocytes show dramatically increased vacuolation and degenerative features, including myofibrillar disruption and lipofuscin accumulation. In brain, pale granular neurons and neurons with lipofuscin-like granules may be seen. Danon disease is caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein 2 (LAMP-2), a single-spanned transmembrane protein localized in the limiting membranes of lysosomes and late endosomes. Most mutations lead to splicing defects or protein truncation, resulting in a loss of transmembrane and/or cytoplasmic domains, leading to LAMP-2 protein deficiency. LAMP-2 is required for the maturation of autophagosomes by fusion with lysosomes; therefore, LAMP-2 deficiency leads to a failure in macroautophagy. There are three LAMP-2 isoforms, LAMP-2A, -2B, and -2C. Clinical features of Danon disease are thought to be mediated by loss of the LAMP-2B isoform which is the major isoform expressed in muscle. It is also known that LAMP-2 plays a role in chaperone-mediated autophagy and RNA- and DNA-targeting autophagy. However, the precise pathophysiological mechanism through which LAMP-2 deficiency causes Danon disease is still not fully understood and its elucidation would promote the development of new therapies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Boucek D, Jirikowic J, Taylor M (2011) Natural history of Danon disease. Genet Med 13:563–568
Cuervo AM, Dice JF (1996) A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273:501–503
Cuervo AM, Dice JF (2000) Regulation of lamp2a levels in the lysosomal membrane. Traffic 1:570–583
Danon MJ, Oh SJ, DiMauro S et al (1981) Lysosomal glycogen storage disease with normal acid maltase. Neurology 31:51–57
Eskelinen EL, Cuervo AM, Taylor MR et al (2005) Unifying nomenclature for the isoforms of the lysosomal membrane protein LAMP-2. Traffic 6:1058–1061
Eskelinen EL, Tanaka Y, Saftig P (2003) At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13:137–145
Eskelinen EL, Illert AL, Tanaka Y et al (2002) Role of LAMP-2 in lysosome biogenesis and autophagy. Mol Biol Cell 13:3355–3368
Eskelinen EL, Schmidt CK, Neu S et al (2004) Disturbed cholesterol traffic but normal proteolytic function in LAMP-1/LAMP-2 double-deficient fibroblasts. Mol Biol Cell 15:3132–3145
Fujiwara Y, Furuta A, Kikuchi H et al (2013) Discovery of a novel type of autophagy targeting RNA. Autophagy 9:403–409
Fujiwara Y, Kikuchi H, Aizawa S et al (2013) Direct uptake and degradation of DNA by lysosomes. Autophagy 9:1167–1671
Fukuda M (1994) Biogenesis of the lysosomal membrane. Subcell Biochem 22:199–230
Furuno K, Ishikawa T, Akasaki K et al (1989) Morphological localization of a major lysosomal membrane glycoprotein in the endocytic membrane system. J Biochem 106:708–716
Furuta A, Wakabayashi K, Haratake J et al (2013) Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease. Acta Neuropathol 125:459–461
Gough NR, Hatem CL, Fambrough DM (1995) The family of LAMP-2 proteins arises by alternative splicing from a single gene: characterization of the avian LAMP-2 gene and identification of mammalian homologs of LAMP-2b and LAMP-2c. DNA Cell Biol 14:863–867
Harrison RE, Bucci C, Vieira OV, Schroer TA, Grinstein S (2003) Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol Cell Biol 23:6494–6506
Hatem CL, Gough NR, Fambrough DM (1995) Multiple mRNAs encode the avian lysosomal membrane protein LAMP-2, resulting in alternative transmembrane and cytoplasmic domains. J Cell Sci 108:2093–2100
Huynh KK, Eskelinen EL, Scott CC, Malevanets A, Saftig P, Grinstein S (2007) LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J 26:313–324
Jäger S, Bucci C, Tanida I et al (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117:4837–4848
Konecki DS, Foetisch K, Zimmer KP, Schlotter M, Lichter-Konecki U (1995) 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
Lippincott-Schwartz J, Fambrough DM (1987) Cycling of the integral membrane glycoprotein, LEP100, between plasma membrane and lysosomes: kinetic and morphological analysis. Cell 49:669–677
Malicdan MC, Noguchi S, Nonaka I, Saftig P, Nishino I (2008) Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord 18:521–529
Malicdan MC, Nishino I (2012) Autophagy in lysosomal myopathies. Brain Pathol 22:82–88
Matsunaga K, Saitoh T, Tabata K et al (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396
Nemazanyy I, Blaauw B, Paolini C et al (2013) Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease. EMBO Mol Med 5:870–890
Nishino I, Fu J, Tanji K et al (2000) Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:906–910
Nishino I (2006) Autophagic vacuolar myopathy. Semin Pediatr Neurol 13:90–95
Nishino I (2003) Autophagic vacuolar myopathies. Curr Neurol and Neurosci Rep 3:64–69
Saftig P, Tanaka Y, Lüllmann-Rauch R, von Figura K (2001) Disease model: LAMP-2 enlightens Danon disease. Trends Mol Med 7:37–39
Schneede A, Schmidt CK, Hölttä-Vuori M et al (2011) Role for LAMP-2 in endosomal cholesterol transport. J Cell Mol Med 15:280–295
Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD (1993) Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260:88–91
Stypmann J, Janssen PM, Prestle J et al (2006) LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling. Basic Res Cardiol 101:281–291
Sugie K, Yamamoto A, Murayama K et al (2002) Clinicopathological features of genetically confirmed Danon disease. Neurology 58:1773–1778
Sugie K, Noguchi S, Kozuka Y et al (2005) Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. J Neuropathol Exp Neurol 64:513–522
Tanaka Y, Guhde G, Suter A et al (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–906
Zhong Y, Wang QJ, Li X et al (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11:468–476
Acknowledgments
This study was supported by Intramural Research Grant (26-8) for Neurological and Psychiatric Disorders of NCNP, Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor, and Welfare. The authors thank Professor Ikuya Nonaka for his help in electron microscopy analysis, and Ms. Megumu Ogawa and Ms. Kaoru Tatezawa for their technical assistance.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Endo, Y., Furuta, A. & Nishino, I. Danon disease: a phenotypic expression of LAMP-2 deficiency. Acta Neuropathol 129, 391–398 (2015). https://doi.org/10.1007/s00401-015-1385-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-015-1385-4