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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.

SUBMITTER: Jenkinson EM

PROVIDER: S-EPMC5045717 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

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

Nature genetics 20160829 10

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 ...[more]

PMID: 27571260

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Project description:BACKGROUND AND PURPOSE:Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS:Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS:All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS:Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.

Dataset Information

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

Publications

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

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