title: Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.
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.
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Emma M
authors: EM
authors: Jenkinson
authors: Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.
authors: Mathieu P
authors: MP
authors: Rodero
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Paul R
authors: PR
authors: Kasher
authors: Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.
authors: Carolina
authors: C
authors: Uggenti
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Anthony
authors: A
authors: Oojageer
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Laurence C
authors: LC
authors: Goosey
authors: Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.
authors: Yoann
authors: Y
authors: Rose
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Molecular and Cellular Function, University of Manchester, Manchester, UK.
authors: Christopher J
authors: CJ
authors: Kershaw
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Jill E
authors: JE
authors: Urquhart
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Simon G
authors: SG
authors: Williams
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Sanjeev S
authors: SS
authors: Bhaskar
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: James
authors: J
authors: O'Sullivan
authors: Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|Experimental Hematology, Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Gabriela M
authors: GM
authors: Baerlocher
authors: Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|Experimental Hematology, Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors: Monika
authors: M
authors: Haubitz
authors: Repeat Diagnostics, Inc., North Vancouver, British Columbia, Canada.|Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors: Geraldine
authors: G
authors: Aubert
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors: Kristin W
authors: KW
authors: Barañano
authors: Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors: Angela J
authors: AJ
authors: Barnicoat
authors: Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy.
authors: Roberta
authors: R
authors: Battini
authors: Department of Neuropediatrics, Klinikum Weiden, Weiden, Germany.|Department of Neuropediatrics, Klinikum Harlaching, Munich, Germany.
authors: Andrea
authors: A
authors: Berger
authors: Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors: Edward M
authors: EM
authors: Blair
authors: CP Place, PLLC, Plano, Texas, USA.|Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA.
authors: Janice E
authors: JE
authors: Brunstrom-Hernandez
authors: Department of Neuropediatrics, Sozialpädiatrisches Zentrum am EVK Düsseldorf, Düsseldorf, Germany.
authors: Johannes A
authors: JA
authors: Buckard
authors: Metabolic Center, Leuven University Hospitals and KU Leuven, Leuven, Belgium.
authors: David M
authors: DM
authors: Cassiman
authors: Department of Neuropediatrics, Hopital Roger Salengro, Lille, France.
authors: Rosaline
authors: R
authors: Caumes
authors: Paediatric Neurology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.
authors: Duccio M
authors: 0000-0002-1367-6419
authors: DM
authors: Cordelli
authors: Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.|Department of Development and Regeneration, Paediatric Neurology, University of Leuven, Leuven, Belgium.
authors: Liesbeth M
authors: LM
authors: De Waele
authors: Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA.
authors: Alexander J
authors: AJ
authors: Fay
authors: Division of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada.
authors: Patrick
authors: P
authors: Ferreira
authors: Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, UK.
authors: Nicholas A
authors: NA
authors: Fletcher
authors: Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
authors: Alan E
authors: AE
authors: Fryer
authors: Hunter Genetics, Hunter New England Local Health District, Waratah, New South Wales, Australia.|School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
authors: Himanshu
authors: H
authors: Goel
authors: Department of Paediatric Neurology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors: Cheryl A
authors: CA
authors: Hemingway
authors: Department of Pediatrics and Adolescent Medicine, University Medical Center, Georg August University, Göttingen, Germany.
authors: Marco
authors: M
authors: Henneke
authors: Pediatric Neurology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors: Imelda
authors: I
authors: Hughes
authors: Dingley Specialist Children's Centre, Royal Berkshire Hospital, Reading, UK.
authors: Rosalind J
authors: RJ
authors: Jefferson
authors: Department of Paediatric Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors: Ram
authors: R
authors: Kumar
authors: Department of Development and Regeneration, Paediatric Neurology, University of Leuven, Leuven, Belgium.
authors: Lieven
authors: L
authors: Lagae
authors: Department of Paediatric Neurology, CHU Paris-Sud Bicetre, Le Kremlin Bicetre, France.
authors: Pierre G
authors: PG
authors: Landrieu
authors: Neurogenetics Division, Clinics Hospital of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors: Charles M
authors: 0000-0002-2296-6098
authors: CM
authors: Lourenço
authors: Department of Paediatrics, Jersey General Hospital, St Helier, UK.
authors: Timothy J
authors: TJ
authors: Malpas
authors: East Anglian Regional Genetics Service, Addenbrooke's Hospital, Cambridge, UK.
authors: Sarju G
authors: 0000-0003-0446-3435
authors: SG
authors: Mehta
authors: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors: Imke
authors: I
authors: Metz
authors: Hugo Moser Research Institute, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Neurology and Pediatrics, Baltimore, Maryland, USA.
authors: Sakkubai
authors: S
authors: Naidu
authors: Department of Genetics, Tartu University Hospital, Tartu, Estonia.|Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
authors: Katrin
authors: K
authors: Õunap
authors: Epilepsy Center/Paediatric Neurology, DRK Kliniken Berlin-Westend, Berlin, Germany.
authors: Axel
authors: A
authors: Panzer
authors: Department of Paediatric Neurology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors: Prab
authors: P
authors: Prabhakar
authors: Department of Neuroradiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors: Gerardine
authors: G
authors: Quaghebeur
authors: Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.
authors: Raphael
authors: R
authors: Schiffmann
authors: Department of Neurology, University of California at San Francisco, San Francisco, California, USA.
authors: Elliott H
authors: EH
authors: Sherr
authors: Department of Paediatrics, Wexham Park Hospital, Slough, UK.
authors: Kanaga R
authors: KR
authors: Sinnathuray
authors: Neuroradiology Department, Salford Royal NHS Foundation Trust, Salford, UK.
authors: Calvin
authors: C
authors: Soh
authors: Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors: Helen S
authors: HS
authors: Stewart
authors: Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors: John
authors: J
authors: Stone
authors: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors: Hilde
authors: H
authors: Van Esch
authors: Department of Pediatrics-Neonatology, St. Augustinusziekenhuis, Wilrijk, Belgium.
authors: Christine E G
authors: CE
authors: Van Mol
authors: Department of Neurology, George Washington University School of Medicine, Children's National Health System, Washington, DC, USA.|Center for Genetic Medicine Research, George Washington University School of Medicine, Children's National Health System, Washington, DC, USA.
authors: Adeline
authors: A
authors: Vanderver
authors: North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.
authors: Emma L
authors: EL
authors: Wakeling
authors: Department of Child Neurology, University Hospital Southampton NHS Trust, Southampton, UK.
authors: Andrea
authors: A
authors: Whitney
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Molecular and Cellular Function, University of Manchester, Manchester, UK.
authors: Graham D
authors: GD
authors: Pavitt
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Molecular and Cellular Function, University of Manchester, Manchester, UK.
authors: Sam
authors: S
authors: Griffiths-Jones
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors: Gillian I
authors: 0000-0002-4223-0571
authors: GI
authors: Rice
authors: Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors: Patrick
authors: P
authors: Revy
authors: Child Neurology and Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.|Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
authors: Marjo S
authors: MS
authors: van der Knaap
authors: Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.
authors: John H
authors: 0000-0002-4017-0667
authors: JH
authors: Livingston
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Molecular and Cellular Function, University of Manchester, Manchester, UK.
authors: Raymond T
authors: 0000-0001-8764-1289
authors: RT
authors: O'Keefe
authors: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.|Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors: Yanick J
authors: YJ
authors: Crow
mesh_terms: D000293:Adolescent; D000328:Adult; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D059345:Cerebral Small Vessel Diseases / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D015331:Cohort Studies; D003560:Cysts / Q000235:genetics / Q000473:pathology; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D007223:Infant; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020537:RNA, Small Nucleolar / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D020537:RNA, Small Nucleolar