Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy (original) (raw)

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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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Author notes

1. Thomas Cullup and Ay Lin Kho: These authors contributed equally to this work.
2. Mathias Gautel and Heinz Jungbluth: These authors jointly directed this work.

Authors and Affiliations

1. DNA Laboratory, Guy's and St Thomas' Serco Pathology, Guy's Hospital, London, UK
   Thomas Cullup, Frances Smith, Shu Yau & Stephen Abbs
2. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK
   Ay Lin Kho, Birgit Brandmeier & Mathias Gautel
3. Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, London, UK
   Ay Lin Kho, Birgit Brandmeier & Mathias Gautel
4. Division of Metabolism, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cure a Carattere Scientifico, Rome, Italy
   Carlo Dionisi-Vici
5. Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cure a Carattere Scientifico, Rome, Italy
   Carlo Dionisi-Vici & Enrico Bertini
6. Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK
   Zoe Urry & Michael A Simpson
7. Department of Paediatric Neurology, Evelina Children's Hospital, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, London, UK
   Verity McClelland & Heinz Jungbluth
8. Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
   Mohammed Al-Owain
9. Faculty of Medicine, Alfaisal University, Riyadh, Saudi Arabia
   Mohammed Al-Owain
10. Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany
    Stefan Koelker, Christian Koerner & Georg F Hoffmann
11. Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
    Frits A Wijburg & Amber E ten Hoedt
12. Greenwood Genetic Center, Greenville, South Carolina, USA
    R Curtis Rogers
13. Department of Pediatrics, Clinical Genetics and Metabolism, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA
    David Manchester
14. Department of Pediatrics, Tokyo Kita Shakai Hoken Hospital, Tokyo, Japan
    Rie Miyata
15. Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    Masaharu Hayashi
16. Section of Medical Genetics, Mater dei Hospital, Msida, Malta
    Elizabeth Said
17. Department of Anatomy & Cell Biology, University of Malta, Msida, Malta
    Elizabeth Said
18. Department of Paediatrics, Mater dei Hospital, Msida, Malta
    Doriette Soler
19. Institute of Human Genetics, Medical University of Graz, Graz, Austria
    Peter M Kroisel & Christian Windpassinger
20. Division of Pediatric Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA
    Francis M Filloux
21. Department of Pediatrics, Tawam Hospital, Al-Ain, UAE
    Salwa Al-Kaabi & Jozef Hertecant
22. Genetics Department, Hospital Vall d'Hebron, Barcelona, Spain
    Miguel Del Campo
23. Department of Clinical Neuropathology, Academic Neuroscience Centre, King's College Hospital, London, UK
    Stefan Buk & Istvan Bodi
24. Department of Neuropathology, Johannes Gutenberg University Medical Centre, Mainz, Germany
    Hans-Hilmar Goebel
25. Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, UK
    Caroline A Sewry
26. Department of Clinical Genetics, Guy's Hospital, London, UK
    Shehla Mohammed & Dragana Josifova
27. Clinical Neuroscience Division, Institute of Psychiatry, King's College London, London, UK
    Heinz Jungbluth

Authors

1. Thomas Cullup
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2. Ay Lin Kho
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3. Carlo Dionisi-Vici
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4. Birgit Brandmeier
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5. Frances Smith
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6. Zoe Urry
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7. Michael A Simpson
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8. Shu Yau
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9. Enrico Bertini
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10. Verity McClelland
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11. Mohammed Al-Owain
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12. Stefan Koelker
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13. Christian Koerner
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14. Georg F Hoffmann
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15. Frits A Wijburg
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16. Amber E ten Hoedt
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17. R Curtis Rogers
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18. David Manchester
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19. Rie Miyata
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20. Masaharu Hayashi
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21. Elizabeth Said
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22. Doriette Soler
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23. Peter M Kroisel
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24. Christian Windpassinger
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25. Francis M Filloux
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26. Salwa Al-Kaabi
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27. Jozef Hertecant
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28. Miguel Del Campo
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29. Stefan Buk
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30. Istvan Bodi
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31. Hans-Hilmar Goebel
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32. Caroline A Sewry
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33. Stephen Abbs
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34. Shehla Mohammed
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35. Dragana Josifova
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36. Mathias Gautel
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37. Heinz Jungbluth
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Contributions

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.

Corresponding authors

Correspondence toMathias Gautel or Heinz Jungbluth.

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The authors declare no competing financial interests.

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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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• Received: 20 April 2012
• Accepted: 15 November 2012
• Published: 09 December 2012
• Issue Date: January 2013
• DOI: https://doi.org/10.1038/ng.2497