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Nat Genet. 2013 Jan;45(1):83-7. doi: 10.1038/ng.2497. Epub 2012 Dec 9.

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

Author information

1
DNA Laboratory, Guy's and St Thomas' Serco Pathology, Guy's Hospital, London, UK.

Abstract

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.

PMID:
23222957
PMCID:
PMC4012842
DOI:
10.1038/ng.2497
[Indexed for MEDLINE]
Free PMC Article

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