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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    • "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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    • "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]. "

    Full-text · Article · Jun 2014 · Neuromuscular Disorders
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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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