Article | Published:

Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Nature Genetics volume 48, pages 11851192 (2016) | Download Citation

  • A Corrigendum to this article was published on 31 January 2017

This article has been updated

Abstract

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

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  • 19 September 2016

    In the version of this article initially published, the names of authors Geraldine Aubert, Gerardine Quaghebeur and Yoann Rose were misspelled. The error has been corrected in the print, HTML and PDF versions of the article.

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Acknowledgements

We are very grateful to the affected families for their involvement in our research. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. DNA panels from the NINDS Human Genetics Resource Center DNA and Cell Line Repository were used in this study, as well as clinical data. The submitters who contributed samples are acknowledged in detailed descriptions of each panel: NDPT099 and NDPT095. Y.J.C. acknowledges funding from the Newlife Foundation (14-15/15), the Great Ormond Street Hospital Children's Charity (V1212) and a state subsidy managed by the National Research Agency (France) under 'Investments for the Future' (ANR-10-IAHU-01). R.T.O'K. acknowledges the Wellcome Trust (104981). This work was supported by Wellcome Trust funding (097820/Z/11/B) to Y.J.C. and R.T.O'K. P.R. has received research support from La Ligue (Equipe Lab Elisée) and the Centre National de la Recherche Scientifique (CNRS). This paper is dedicated to the memory of John L. Tolmie.

Author information

Affiliations

  1. Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.

    • Emma M Jenkinson
    • , Paul R Kasher
    • , Anthony Oojageer
    • , Laurence C Goosey
    • , Jill E Urquhart
    • , Simon G Williams
    • , Sanjeev S Bhaskar
    • , James O'Sullivan
    • , Gillian I Rice
    •  & Yanick J Crow
  2. Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.

    • Mathieu P Rodero
    • , Carolina Uggenti
    • , Yoann Rose
    •  & Yanick J Crow
  3. Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Molecular and Cellular Function, University of Manchester, Manchester, UK.

    • Christopher J Kershaw
    • , Graham D Pavitt
    • , Sam Griffiths-Jones
    •  & Raymond T O'Keefe
  4. Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

    • Gabriela M Baerlocher
    •  & Monika Haubitz
  5. Experimental Hematology, Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

    • Gabriela M Baerlocher
    •  & Monika Haubitz
  6. Repeat Diagnostics, Inc., North Vancouver, British Columbia, Canada.

    • Geraldine Aubert
  7. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Geraldine Aubert
  8. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kristin W Barañano
  9. Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.

    • Kristin W Barañano
  10. Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

    • Angela J Barnicoat
  11. Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy.

    • Roberta Battini
  12. Department of Neuropediatrics, Klinikum Weiden, Weiden, Germany.

    • Andrea Berger
  13. Department of Neuropediatrics, Klinikum Harlaching, Munich, Germany.

    • Andrea Berger
  14. Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

    • Edward M Blair
    •  & Helen S Stewart
  15. CP Place, PLLC, Plano, Texas, USA.

    • Janice E Brunstrom-Hernandez
  16. Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA.

    • Janice E Brunstrom-Hernandez
    •  & Alexander J Fay
  17. Department of Neuropediatrics, Sozialpädiatrisches Zentrum am EVK Düsseldorf, Düsseldorf, Germany.

    • Johannes A Buckard
  18. Metabolic Center, Leuven University Hospitals and KU Leuven, Leuven, Belgium.

    • David M Cassiman
  19. Department of Neuropediatrics, Hopital Roger Salengro, Lille, France.

    • Rosaline Caumes
  20. Paediatric Neurology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.

    • Duccio M Cordelli
  21. Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.

    • Liesbeth M De Waele
  22. Department of Development and Regeneration, Paediatric Neurology, University of Leuven, Leuven, Belgium.

    • Liesbeth M De Waele
    •  & Lieven Lagae
  23. Division of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada.

    • Patrick Ferreira
  24. Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, UK.

    • Nicholas A Fletcher
  25. Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.

    • Alan E Fryer
  26. Hunter Genetics, Hunter New England Local Health District, Waratah, New South Wales, Australia.

    • Himanshu Goel
  27. School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.

    • Himanshu Goel
  28. Department of Paediatric Neurology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

    • Cheryl A Hemingway
    •  & Prab Prabhakar
  29. Department of Pediatrics and Adolescent Medicine, University Medical Center, Georg August University, Göttingen, Germany.

    • Marco Henneke
  30. Pediatric Neurology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.

    • Imelda Hughes
  31. Dingley Specialist Children's Centre, Royal Berkshire Hospital, Reading, UK.

    • Rosalind J Jefferson
  32. Department of Paediatric Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.

    • Ram Kumar
  33. Department of Paediatric Neurology, CHU Paris–Sud Bicetre, Le Kremlin Bicetre, France.

    • Pierre G Landrieu
  34. Neurogenetics Division, Clinics Hospital of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

    • Charles M Lourenço
  35. Department of Paediatrics, Jersey General Hospital, St Helier, UK.

    • Timothy J Malpas
  36. East Anglian Regional Genetics Service, Addenbrooke's Hospital, Cambridge, UK.

    • Sarju G Mehta
  37. Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.

    • Imke Metz
  38. Hugo Moser Research Institute, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Neurology and Pediatrics, Baltimore, Maryland, USA.

    • Sakkubai Naidu
  39. Department of Genetics, Tartu University Hospital, Tartu, Estonia.

    • Katrin Õunap
  40. Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

    • Katrin Õunap
  41. Epilepsy Center/Paediatric Neurology, DRK Kliniken Berlin-Westend, Berlin, Germany.

    • Axel Panzer
  42. Department of Neuroradiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

    • Gerardine Quaghebeur
  43. Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.

    • Raphael Schiffmann
  44. Department of Neurology, University of California at San Francisco, San Francisco, California, USA.

    • Elliott H Sherr
  45. Department of Paediatrics, Wexham Park Hospital, Slough, UK.

    • Kanaga R Sinnathuray
  46. Neuroradiology Department, Salford Royal NHS Foundation Trust, Salford, UK.

    • Calvin Soh
  47. Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • John Stone
  48. Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

    • Hilde Van Esch
  49. Department of Pediatrics–Neonatology, St. Augustinusziekenhuis, Wilrijk, Belgium.

    • Christine E G Van Mol
  50. Department of Neurology, George Washington University School of Medicine, Children's National Health System, Washington, DC, USA.

    • Adeline Vanderver
  51. Center for Genetic Medicine Research, George Washington University School of Medicine, Children's National Health System, Washington, DC, USA.

    • Adeline Vanderver
  52. North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.

    • Emma L Wakeling
  53. Department of Child Neurology, University Hospital Southampton NHS Trust, Southampton, UK.

    • Andrea Whitney
  54. Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.

    • Patrick Revy
  55. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.

    • Patrick Revy
    •  & Yanick J Crow
  56. Child Neurology and Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.

    • Marjo S van der Knaap
  57. Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.

    • Marjo S van der Knaap
  58. Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.

    • John H Livingston

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Contributions

Exome sequencing was performed by J.E.U., J.O'S., S.G.W. and S.S.B. Exome and genomic capture data were analyzed by E.M.J. Linkage analysis was undertaken by J.E.U. Sanger sequencing and cloning were performed by E.M.J. with assistance from A.O. and L.C.G. Copy number analysis and microsatellite genotyping were undertaken by E.M.J. Cell lines were maintained by E.M.J., A.O., L.C.G., M.P.R. and Y.R. In vitro transcription of U8 snoRNA, EMSAs, 3′-end processing assays, luciferase assays and polysome assays were performed by E.M.J., C.J.K. and R.T.O'K. with assistance from G.D.P. Cell proliferation, senescence and apoptosis assays were performed by M.P.R. DNA content and ImmuoFISH assays were undertaken by M.P.R. with assistance from P.R. Immunoblotting was performed by P.R.K. RT–PCR was performed by M.P.R. with assistance from G.I.R. RNA modeling studies were performed by S.G.-J. Telomere analysis was undertaken by G.M.B., M. Haubitz and G.A. Y.J.C. and R.T.O'K. designed and supervised the project and wrote the manuscript supported by G.I.R. and E.M.J. M.S.v.d.K., J.H.L. and Y.J.C. reviewed the patient scans. K.W.B., A.J.B., R.B., A.B., J.E.B.-H., J.A.B., D.M. Cassiman, R.C., D.M. Cordelli, L.M.D.W., A.J.F., P.F., N.A.F., A.E.F., H.G., C.A.H., I.H., R.J.J., R.K., G.Q., L.L., C.M.L., T.J.M., S.G.M., I.M., S.N., K.Õ., P.P., R.S., E.H.S., C.S., H.S.S., J.S., C.U., H.V.E., C.E.G.V.M., A.V., E.L.W., E.M.B., P.G.L., A.P., K.R.S., M. Haubitz, M. Henneke and A.W. identified affected patients or assisted with related clinical and laboratory studies.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yanick J Crow.

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DOI

https://doi.org/10.1038/ng.3661

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