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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)83-87
Number of pages5
JournalNature Genetics
Volume45
Issue number1
DOIs
Publication statusPublished - Jan 2013

ASJC Scopus subject areas

  • Genetics

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