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

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

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.