Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts
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| Název: | Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts |
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| Autoři: | Siobhan Crilly, Denis L. J. Lafontaine, Ludivine Wacheul, Emma M. Jenkinson, Gillian I. Rice, Carolina Uggenti, Paul R. Kasher, Yanick J. Crow, Andrew P. Badrock, Raymond T. O'Keefe |
| Zdroj: | American journal of human genetics, 106 (5 Badrock, A P, Uggenti, C, Wacheul, L, Crilly, S, Jenkinson, E M, Rice, G I, Kasher, P R, Lafontaine, D L J, Crow, Y J & O'Keefe, R T 2020, ' Analysis of U8 snoRNA Variants in Zebrafish Reveals how Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts ', American Journal of Human Genetics, vol. 106, no. 5, pp. 694-706 . https://doi.org/10.1016/j.ajhg.2020.04.003 Badrock, A, Uggenti, C, Wacheul, L, Crilly, S, Jenkinson, E, Rice, G, Kasher, P, Lafontaine, D, Crow, Y & O'Keefe, R 2020, 'Analysis of U8 snoRNA Variants in Zebrafish Reveals how Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts', American Journal of Human Genetics, vol. 106, no. 5, pp. 694-706. https://doi.org/10.1016/j.ajhg.2020.04.003 |
| Informace o vydavateli: | Elsevier BV, 2020. |
| Rok vydání: | 2020 |
| Témata: | 0301 basic medicine, Génétique clinique, Embryonic Development, ribosomopathy, snoRNA, SNORD118, U8 snoRNA, 03 medical and health sciences, Leukoencephalopathies, Zebrafish Proteins/genetics, Embryonic Development/genetics, Small Nucleolar/genetics, Animals, Humans, RNA, Small Nucleolar, Central Nervous System Cysts/genetics, Central Nervous System Cysts, Alleles, Conserved Sequence, Zebrafish, 0303 health sciences, Leukoencephalopathies/genetics, Base Sequence, Animal, Cysts, Calcinosis/genetics, Cysts/genetics, Calcinosis, Zebrafish Proteins, zebrafish, 3. Good health, Disease Models, Animal, Disease Models, Mutation, RNA, Tumor Suppressor Protein p53/genetics, Zebrafish/embryology, Labrune syndrome, Tumor Suppressor Protein p53, Biologie, RNA, Small Nucleolar/genetics, leukoencephalopathy with calcifications and cysts |
| Popis: | 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. |
| Druh dokumentu: | Article |
| Popis souboru: | 1 full-text file(s): application/pdf; application/octet-stream; application/pdf |
| Jazyk: | English |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2020.04.003 |
| Přístupová URL adresa: | http://www.cell.com/article/S0002929720301129/pdf https://pubmed.ncbi.nlm.nih.gov/32359472 https://research.manchester.ac.uk/en/publications/cf6ab27e-3ac6-4fc6-bd3b-aea378e05417 https://doi.org/10.1016/j.ajhg.2020.04.003 https://www.sciencedirect.com/science/article/pii/S0002929720301129 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212298 https://www.research.manchester.ac.uk/portal/en/publications/analysis-of-u8-snorna-variants-in-zebrafish-reveals-how-biallelic-variants-cause-leukoencephalopathy-with-calcifications-and-cysts(cf6ab27e-3ac6-4fc6-bd3b-aea378e05417).html https://pubmed.ncbi.nlm.nih.gov/32359472/ https://www.ncbi.nlm.nih.gov/pubmed/32359472 https://www.cell.com/ajhg/fulltext/S0002-9297(20)30112-9 http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/307345 https://hdl.handle.net/20.500.11820/97a46b3b-bad9-48c1-98d3-eee1326b8a59 https://www.pure.ed.ac.uk/ws/files/142014222/BW1OWN_O https://pure.manchester.ac.uk/ws/files/162365839/Badrock_et_al_AJHG_revision_final_changes_accepted_for_PURE.pdf https://research.manchester.ac.uk/en/publications/cf6ab27e-3ac6-4fc6-bd3b-aea378e05417 https://doi.org/10.1016/j.ajhg.2020.04.003 |
| Rights: | Elsevier Non-Commercial |
| Přístupové číslo: | edsair.doi.dedup.....849cb23302137c98d55f60d6c34d5a35 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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. |
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| ISSN: | 00029297 |
| DOI: | 10.1016/j.ajhg.2020.04.003 |