دورية أكاديمية
Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts.
| العنوان: | Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts. |
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| المؤلفون: | Badrock AP; Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. Electronic address: andrew.badrock@igmm.ed.ac.uk., Uggenti C; Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK; Université de Paris, Paris, France; Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France., Wacheul L; RNA Molecular Biology, ULB Cancer Research Center (U-CRC), Center for Microscopy and Molecular Imaging (CMMI), Fonds de la Recherche Scientifique (F.R.S.-FNRS), Université Libre de Bruxelles (ULB), BioPark Campus, B-6041, Gosselies, Belgium., Crilly S; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, M13 9PT, UK., Jenkinson EM; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK., Rice GI; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK., Kasher PR; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, M13 9PT, UK., Lafontaine DLJ; RNA Molecular Biology, ULB Cancer Research Center (U-CRC), Center for Microscopy and Molecular Imaging (CMMI), Fonds de la Recherche Scientifique (F.R.S.-FNRS), Université Libre de Bruxelles (ULB), BioPark Campus, B-6041, Gosselies, Belgium., Crow YJ; Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK; Université de Paris, Paris, France; Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France., O'Keefe RT; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Electronic address: rokeefe@manchester.ac.uk. |
| المصدر: | American journal of human genetics [Am J Hum Genet] 2020 May 07; Vol. 106 (5), pp. 694-706. Date of Electronic Publication: 2020 Apr 30. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2008- : [Cambridge, MA] : Cell Press Original Publication: Baltimore, American Society of Human Genetics. |
| مواضيع طبية MeSH: | Alleles* , Mutation*, Calcinosis/*genetics , Central Nervous System Cysts/*genetics , Cysts/*genetics , Leukoencephalopathies/*genetics , RNA, Small Nucleolar/*genetics , Zebrafish/*genetics, Animals ; Base Sequence ; Calcinosis/pathology ; Central Nervous System Cysts/pathology ; Conserved Sequence ; Disease Models, Animal ; Embryonic Development/genetics ; Humans ; Leukoencephalopathies/pathology ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Zebrafish/embryology ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism |
| مستخلص: | How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which monitors ribosome biogenesis. Further, we demonstrate that fibroblasts from individuals with LCC are defective in rRNA processing. Human precursor-U8 (pre-U8) containing a 3' extension rescued mutant U8 zebrafish, and this result indicates conserved biological function. Analysis of LCC-associated U8 mutations in zebrafish revealed that one null and one functional allele contribute to LCC. We show that mutations in three nucleotides at the 5' end of pre-U8 alter the processing of the 3' extension, and we identify a previously unknown base-pairing interaction between the 5' end and the 3' extension of human pre-U8. Indeed, LCC-associated mutations in any one of seven nucleotides in the 5' end and 3' extension alter the processing of pre-U8, and these mutations are present on a single allele in almost all individuals with LCC identified to date. Given genetic data indicating that bi-allelic null U8 alleles are likely incompatible with human development, and that LCC is not caused by haploinsufficiency, the identification of hypomorphic misprocessing mutations that mediate viable embryogenesis furthers our understanding of LCC molecular pathology and cerebral vascular homeostasis. (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.) |
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| فهرسة مساهمة: | Keywords: Labrune syndrome; SNORD118; U8 snoRNA; leukoencephalopathy with calcifications and cysts; ribosomopathy; snoRNA; zebrafish |
| المشرفين على المادة: | 0 (Leukoencephalopathy Brain Calcifications and Cysts) 0 (RNA, Small Nucleolar) 0 (Tumor Suppressor Protein p53) 0 (Zebrafish Proteins) 0 (tp53 protein, zebrafish) |
| تواريخ الأحداث: | Date Created: 20200504 Date Completed: 20200727 Latest Revision: 20201107 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC7212298 |
| DOI: | 10.1016/j.ajhg.2020.04.003 |
| PMID: | 32359472 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1537-6605 |
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| DOI: | 10.1016/j.ajhg.2020.04.003 |