title: Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.
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.
authors.affiliation: DNA Laboratory, Guy's and St Thomas' Serco Pathology, Guy's Hospital, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cullup
authors.forename: Ay Lin
authors.initials: AL
authors.lastname: Kho
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Birgit
authors.initials: B
authors.lastname: Brandmeier
authors.forename: Frances
authors.initials: F
authors.lastname: Smith
authors.forename: Zoe
authors.initials: Z
authors.lastname: Urry
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Shu
authors.initials: S
authors.lastname: Yau
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Verity
authors.initials: V
authors.lastname: McClelland
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.forename: Stefan
authors.initials: S
authors.lastname: Koelker
authors.forename: Christian
authors.initials: C
authors.lastname: Koerner
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Amber E
authors.initials: AE
authors.lastname: ten Hoedt
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Rogers
authors.forename: David
authors.initials: D
authors.lastname: Manchester
authors.forename: Rie
authors.initials: R
authors.lastname: Miyata
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Said
authors.forename: Doriette
authors.initials: D
authors.lastname: Soler
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kroisel
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.forename: Francis M
authors.initials: FM
authors.lastname: Filloux
authors.forename: Salwa
authors.initials: S
authors.lastname: Al-Kaabi
authors.forename: Jozef
authors.initials: J
authors.lastname: Hertecant
authors.forename: Miguel
authors.initials: M
authors.lastname: Del Campo
authors.forename: Stefan
authors.initials: S
authors.lastname: Buk
authors.forename: Istvan
authors.initials: I
authors.lastname: Bodi
authors.forename: Hans-Hilmar
authors.initials: HH
authors.lastname: Goebel
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifova
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D001706:Biopsy; D002386:Cataract / Q000235:genetics*; D003241:Consanguinity; D059472:Exome; D005190:Family; D005808:Genes, Recessive; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D011506:Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D000951:Antigens, Neoplasm; D000071183:Autophagy-Related Proteins; C000592185:EPG5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051907:Lysosomal Membrane Proteins; C549756:NBR1 protein, human; D011506:Proteins; D033921:Vesicular Transport Proteins