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.
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Acknowledgements
We are grateful to the individuals with Vici syndrome and their families for their participation in this study. We would like to thank our colleagues at the Genomics Facility of the Comprehensive Biomedical Research Centre of Guy's and St Thomas' NHS Foundation Trust for their support. We would also like to thank the physicians D. Creel, R.O. Hoffman and L. Al-Gazali for their input and productive discussions. H.J. was supported by a grant from the Guy's and St Thomas' Charitable Foundation (grant 070404). M.G. and A.L.K. were supported by the Leducq Foundation Transatlantic Network Proteotoxicity (11 CVD 04) and the Medical Research Council of Great Britain (MR/J010456/1). M.G. holds the British Heart Foundation Chair of Molecular Cardiology. H.J. would like to dedicate this work to the memory of Rahul Ghosh, his first patient with Vici syndrome.
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T.C. designed the experiments, performed whole-exome capture, Sanger sequencing, cDNA sequencing and quantitative PCR (qPCR) analysis, analyzed data and wrote the manuscript. A.L.K. and B.B. performed immunostaining, confocal microscopy, cell culture studies and protein blotting. Z.U. performed qPCR analysis. F.S., M.A.S., S.Y. and S.A. prepared and performed whole-exome capture and analyzed the exome sequencing data. C.D.-V., E.B., V.M., M.A.-O., S.K., C.K., G.F.H., F.A.W., A.E.t.H., R.C.R., D.M., R.M., M.H., E.S., D.S., P.M.K., C.W., F.M.F., S.A.-K., J.H. and M.D.C. provided clinical data. S.B., I.B., H.-H.G. and C.A.S. provided and analyzed neuropathological data. S.M. and D.J. provided clinical data and oversaw genetic aspects of the research. M.G. analyzed data obtained from immunostaining, confocal microscopy, cell culture studies and protein blotting and wrote the manuscript. H.J. provided clinical and neuropathological data, analyzed exome and Sanger sequencing data, oversaw all aspects of the research and wrote the manuscript.
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Cullup, T., Kho, A., Dionisi-Vici, C. et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet 45, 83–87 (2013). https://doi.org/10.1038/ng.2497
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DOI: https://doi.org/10.1038/ng.2497
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