Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

Abstract

Danon disease is a rare, severe X-linked form of cardiomyopathy caused by deficiency of lysosome-associated membrane protein 2 (LAMP-2). Other clinical manifestations include skeletal myopathy, cognitive defects and visual problems. Although individuals with Danon disease have been clinically described since the early 1980s, the underlying molecular mechanisms involved in pathological progression remain poorly understood. LAMP-2 is known to be involved in autophagy, and a characteristic accumulation of autophagic vacuoles in the affected tissues further supports the idea that autophagy is disrupted in this disease. The LAMP2 gene is alternatively spliced to form three splice isoforms, which are thought to play different autophagy-related cellular roles. This Commentary explores findings from genetic, histological, functional and tissue expression studies that suggest that the specific loss of the LAMP-2B isoform, which is likely to be involved in macroautophagy, plays a crucial role in causing the Danon phenotype. We also compare findings from mouse and cellular models, which have allowed for further molecular characterization but have also shown phenotypic differences that warrant attention. Overall, there is a need to better functionally characterize the LAMP-2B isoform in order to rationally explore more effective therapeutic options for individuals with Danon disease.

Review: Danon disease: Review of natural history and recent advances

“…The remaining part of exon 9 encodes a transmembrane domain (24 amino acids) and a cytoplasmic tail (11 amino acids). Exon 9 undergoes alternative splicing, resulting in three different spliced isoforms, LAMP‐2a, LAMP‐2b and LAMP‐2c, which share the same luminal domain but have both different transmembrane and cytoplasmic domains (the cytoplasmic domain is the most relevant to understanding the variability of clinical manifestations) and different tissue distribution and functions in the autophagy degradation pathway (Table , Figure ).…”

“…DD was originally postulated to be caused by a glycogen storage defect of glycogen accumulation in lysosomes. However, recent studies have shown that the underlying mechanism is a block in autophagy leading to impaired fusion of autophagosome–lysosome and/or inefficient lysosome biogenesis and maturation .…”

Genetic Infiltrative Cardiomyopathies

“…86 However, continued genetic and cellular studies have suggested that it is instead a disease of deficient autophagy that leads to glycogen accumulation. 87,88 …”

“…88 Although most described mutations in LAMP2 affect all 3 isoforms, there are reports of mutations that only affect the LAMP2-B isoform, suggesting that deficiency of this isoform is necessary and sufficient to cause disease. 87,88 For a complete review of the molecular biology of LAMP2 in Danon, see the recent review by Rowland and colleagues 88 (2016). Generally, loss-of-function mutations are associated with an earlier age of onset compared with missense mutations.…”

Studying the pathophysiologic connection between cardiovascular and nervous systems using stem cells

“…As mentioned above, deficiency in LAMP‐2 protein causes lysosomal glycogen storage problems in the affected cell types (e.g., cardiomyocytes and neurons) in Danon patients. Given the function of LAMP‐2 in lysosome biogenesis and autophagy (Rowland et al, ), LAMP‐2 knockout mice displayed accumulation of autophagic vacuoles and cardiomyopathy (Saftig et al, ). iPSC technology made it possible to explore the effects of LAMP‐2 deficiency in human cells.…”