Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts
| Autor: | Emma M. Jenkinson, Andrew P. Badrock, Denis L. J. Lafontaine, Gillian I. Rice, Raymond T. O'Keefe, Siobhan Crilly, Paul R. Kasher, Ludivine Wacheul, Carolina Uggenti, Yanick J. Crow |
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| Rok vydání: | 2020 |
| Předmět: |
Génétique clinique
Ribosomopathy Mutant Ribosome biogenesis ribosomopathy Conserved sequence U8 snoRNA 0302 clinical medicine Leukoencephalopathies Embryonic Development/genetics Central Nervous System Cysts/genetics Central Nervous System Cysts Zebrafish Genetics (clinical) Conserved Sequence Genetics 0303 health sciences Leukoencephalopathies/genetics Cysts Calcinosis Tumor Suppressor Protein p53/genetics Labrune syndrome Haploinsufficiency Biologie leukoencephalopathy with calcifications and cysts Embryonic Development Biology snoRNA Article SNORD118 03 medical and health sciences Zebrafish Proteins/genetics Animals Humans RNA Small Nucleolar Allele RRNA processing Alleles 030304 developmental biology Base Sequence Calcinosis/genetics Cysts/genetics Zebrafish Proteins zebrafish biology.organism_classification Disease Models Animal Mutation Zebrafish/embryology Tumor Suppressor Protein p53 030217 neurology & neurosurgery RNA Small Nucleolar/genetics |
| Zdroj: | Am J Hum Genet 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 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 American journal of human genetics, 106 (5 |
| ISSN: | 1537-6605 |
| DOI: | 10.1016/j.ajhg.2020.04.003 |
| 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. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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