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

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RESEARCH PRODUCT

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

Rie Miyata Hans H. Goebel Miguel Del Campo Salwa Al-kaabi Caroline Sewry Georg F. Hoffmann Peter M. Kroisel Michael A. Simpson Enrico Bertini Stephen Abbs Heinz Jungbluth Heinz Jungbluth Birgit Brandmeier Doriette Soler Jozef Hertecant Masaharu Hayashi Carlo Dionisi-vici Stefan Koelker Frances Smith Shehla Mohammed Verity M Mcclelland Christian Koerner David K. Manchester Amber E. Ten Hoedt Mohammed Al-owain Dragana Josifova Christian Windpassinger Shu Yau Mathias Gautel Stefan Buk Francis Filloux Ay Lin Kho Istvan Bodi R. Curtis Rogers Zoe Urry Elizabeth Said Elizabeth Said Thomas Cullup Frits A. Wijburg

subject

Biopsy Vesicular Transport Proteins Autophagy-Related Proteins Genes Recessive Consanguinity Biology medicine.disease_cause Article Cataract 03 medical and health sciences Consanguinity 0302 clinical medicine Cataracts Antigens Neoplasm Genetics medicine Autophagy Humans Vici syndrome Exome Family Muscle Skeletal Exome Immunodeficiency 030304 developmental biology Genetics 0303 health sciences Mutation Autophagy Intracellular Signaling Peptides and Proteins Lysosome-Associated Membrane Glycoproteins Proteins medicine.disease Mutation Autophagy Protein 5 Agenesis of Corpus Callosum Lysosomes 030217 neurology & neurosurgery

description

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.

year	journal	country	edition	language
2013-01-01	Nature genetics

10.1038/ng.2497 http://europepmc.org/articles/PMC4012842