Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

1] DNA Laboratory, Guy's and St Thomas' Serco Pathology, Guy's Hospital, London, UK. [2].
Nature Genetics (Impact Factor: 29.35). 12/2012; 45(1). DOI: 10.1038/ng.2497
Source: PubMed


Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.

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Available from: Istvan Bodi, Oct 04, 2015
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    • "In agreement with this, reactivation of autophagy restored myofiber survival and ameliorated the dystrophic phenotype of collagen VI null mice. More recently, deregulation of the autophagic process was also demonstrated in other dystrophic mouse models [6]–[9] as well as in the Vici syndrome, a human genetic disease caused by recessive mutations of the EPG5 gene, which codes for a key autophagy regulator involved in the formation of autolysosomes [10]. "
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    ABSTRACT: The essential role of autophagy in muscle homeostasis has been clearly demonstrated by phenotype analysis of mice with muscle-specific inactivation of genes encoding autophagy-related proteins. Ambra1 is a key component of the Beclin 1 complex and, in zebrafish, it is encoded by two paralogous genes, ambra1a and ambra1b, both required for normal embryogenesis and larval development. In this study we focused on the function of Ambra1, a positive regulator of the autophagic process, during skeletal muscle development by means of morpholino (MO)-mediated knockdown and compared the phenotype of zebrafish Ambra1-depleted embryos with that of Ambra1gt/gt mouse embryos. Morphological analysis of zebrafish morphant embryos revealed that silencing of ambra1 impairs locomotor activity and muscle development, as well as myoD1 expression. Skeletal muscles in ATG-morphant embryos displayed severe histopathological changes and contained only small areas of organized myofibrils that were widely dispersed throughout the cell. Double knockdown of ambra1a and ambra1b resulted in a more severe phenotype whereas defects were much less evident in splice-morphants. The morphants phenotypes were effectively rescued by co-injection with human AMBRA1 mRNA. Together, these results indicate that ambra1a and ambra1b are required for the correct development and morphogenesis of skeletal muscle.
    PLoS ONE 06/2014; 9(6):e99210. DOI:10.1371/journal.pone.0099210 · 3.23 Impact Factor
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    • "Clinically, the main diagnostic features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and skin hypopigmentation are almost universally present in EPG5-mutated patients, whereas other organs are more variably involved. An associated myopathy, already suggested in earlier reports by findings of hypotonia, muscle weakness, atrophy and mild to moderate CK elevations, has been recently documented in more detail [59]. On light microscopy, EPG5-related myopathy is characterized by variable degrees of type 1 predominance, type 1 atrophy and fibre type disproportion, central nuclei, vacuoles and increased glycogen storage [58]. "
    Neuromuscular Disorders 06/2014; 24(6). DOI:10.1016/j.nmd.2014.03.009 · 2.64 Impact Factor
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    • "In agreement with the role of EPG5, myofibers and fibroblasts of Vici patients display an accumulation of the autophagy adaptors p62 (also known as SQSTM1) and NBR1, and of lipidated LC3, confirming that the autophagy pathway is blocked (Cullup et al., 2013). Furthermore, the presence of puncta that are positive for LC3 and p62, together with a reduced colocalization of LC3 with the lysosomal receptor for CMA, LAMP1, suggests that the fusion of autophagosomes with lysosomes is blocked in these patients (Cullup et al., 2013). These data have been confirmed by the phenotype of Epg5- knockout mice; deletion of Epg5 leads to selective damage of cortical layer 5 pyramidal neurons and spinal cord motor neurons, which result in muscle degeneration, myofiber atrophy and reduced survival (Zhao et al., 2013a). "
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    ABSTRACT: A number of recent studies have highlighted the importance of autophagy and the ubiquitin-proteasome in the pathogenesis of muscle wasting in different types of inherited muscle disorders. Autophagy is crucial for the removal of dysfunctional organelles and protein aggregates, whereas the ubiquitin-proteasome is important for the quality control of proteins. Post-mitotic tissues, such as skeletal muscle, are particularly susceptible to aged or dysfunctional organelles and aggregation-prone proteins. Therefore, these degradation systems need to be carefully regulated in muscles. Indeed, excessive or defective activity of the autophagy lysosome or ubiquitin-proteasome leads to detrimental effects on muscle homeostasis. A growing number of studies link abnormalities in the regulation of these two pathways to myofiber degeneration and muscle weakness. Understanding the pathogenic role of these degradative systems in each inherited muscle disorder might provide novel therapeutic targets to counteract muscle wasting. In this Commentary, we will discuss the current view on the role of autophagy lysosome and ubiquitin-proteasome in the pathogenesis of myopathies and muscular dystrophies, and how alteration of these degradative systems contribute to muscle wasting in inherited muscle disorders. We will also discuss how modulating autophagy and proteasome might represent a promising strategy for counteracting muscle loss in different diseases.
    Journal of Cell Science 12/2013; 126(Pt 23):5325-33. DOI:10.1242/jcs.114041 · 5.43 Impact Factor
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