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

Jenkinson, Emma M; Rodero, Mathieu P; Kasher, Paul R; Uggenti, Carolina; Oojageer, Anthony; Goosey, Laurence C; Rose, Yohann; Kershaw, Christopher J; Urquhart, Jill E; Williams, Simon G; Bhaskar, Sanjeev S; O'Sullivan, James; Baerlocher, Gabriela M; Haubitz, Monika; Aubert, Gerardine; Barañano, Kristin W; Barnicoat, Angela J; Battini, Roberta; Berger, Andrea; Blair, Edward M; Brunstrom-Hernandez, Janice E; Buckard, Johannes A; Cassiman, David; Caumes, Rosaline; Cordelli, Duccio M; De Waele, Liesbeth; Fay, Alexander J; Ferreira, Patrick; Fletcher, Nicholas A; Fryer, Alan E; Goel, Himanshu; Hemingway, Cheryl A; Henneke, Marco; Hughes, Imelda; Jefferson, Rosalind J; Kumar, Ram; Lagae, Lieven; Landrieu, Pierre G; Lourenço, Charles M; Malpas, Timothy J; Mehta, Sarju G; Metz, Imke; Naidu, Sakkubai; Õunap, Katrin; Panzer, Axel; Prabhakar, Prab; Quaghebeur, Geraldine; Schiffmann, Raphael; Sherr, Elliott H; Sinnathuray, Kanaga R; Soh, Calvin; Stewart, Helen S; Stone, John; Van Esch, Hilde; Van Mol, Christine EG; Vanderver, Adeline; Wakeling, Emma L; Whitney, Andrea; Pavitt, Graham D; Griffiths-Jones, Sam; Rice, Gillian I; Revy, Patrick; van der Knaap, Marjo S; Livingston, John H; O'Keefe, Raymond T; Crow, Yanick J

doi:10.1038/ng.3661

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

Author:

Jenkinson, Emma M

Rodero, Mathieu P ; Kasher, Paul R ; Uggenti, Carolina ; Oojageer, Anthony ; Goosey, Laurence C ; Rose, Yohann ; Kershaw, Christopher J ; Urquhart, Jill E ; Williams, Simon G ; Bhaskar, Sanjeev S ; O'Sullivan, James ; Baerlocher, Gabriela M ; Haubitz, Monika ; Aubert, Gerardine ; Barañano, Kristin W ; Barnicoat, Angela J ; Battini, Roberta ; Berger, Andrea ; Blair, Edward M ; Brunstrom-Hernandez, Janice E ; Buckard, Johannes A ; Cassiman, David ; Caumes, Rosaline ; Cordelli, Duccio M ; De Waele, Liesbeth ; Fay, Alexander J ; Ferreira, Patrick ; Fletcher, Nicholas A ; Fryer, Alan E ; Goel, Himanshu ; Hemingway, Cheryl A ; Henneke, Marco ; Hughes, Imelda ; Jefferson, Rosalind J ; Kumar, Ram ; Lagae, Lieven ; Landrieu, Pierre G ; Lourenço, Charles M ; Malpas, Timothy J ; Mehta, Sarju G ; Metz, Imke ; Naidu, Sakkubai ; Õunap, Katrin ; Panzer, Axel ; Prabhakar, Prab ; Quaghebeur, Geraldine ; Schiffmann, Raphael ; Sherr, Elliott H ; Sinnathuray, Kanaga R ; Soh, Calvin ; Stewart, Helen S ; Stone, John ; Van Esch, Hilde ; Van Mol, Christine EG ; Vanderver, Adeline ; Wakeling, Emma L ; Whitney, Andrea ; Pavitt, Graham D ; Griffiths-Jones, Sam ; Rice, Gillian I ; Revy, Patrick ; van der Knaap, Marjo S ; Livingston, John H ; O'Keefe, Raymond T ; Crow, Yanick J

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, BOX-C/D, CEREBRORETINAL MICROANGIOPATHY, LSM PROTEINS, COMPONENT 1, U8 SNORNA, IDENTIFICATION, INVOLVEMENT, BIOGENESIS, RIBOSOMES, DISORDER, Adolescent, Adult, Calcinosis, Cell Line, Cerebral Small Vessel Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 17, Cohort Studies, Cysts, Exome, Female, Genetic Linkage, Genome, Human, Humans, Infant, Leukoencephalopathies, Male, Middle Aged, Mutation, RNA, Small Nucleolar, Sequence Analysis, DNA, Young Adult, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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.