ZFIN ID: ZDB-PUB-200504-2
Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts
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.
Date: 2020
Source: American journal of human genetics   106(5): 694-706 (Journal)
Registered Authors: Badrock, Andrew P., Kasher, Paul
Keywords: Labrune syndrome, SNORD118, U8 snoRNA, leukoencephalopathy with calcifications and cysts, ribosomopathy, snoRNA, zebrafish
MeSH Terms:
  • Alleles*
  • Animals
  • Base Sequence
  • Calcinosis/genetics*
  • Calcinosis/pathology
  • Central Nervous System Cysts/genetics*
  • Central Nervous System Cysts/pathology
  • Conserved Sequence
  • Cysts/genetics*
  • Disease Models, Animal
  • Embryonic Development/genetics
  • Humans
  • Leukoencephalopathies/genetics*
  • Leukoencephalopathies/pathology
  • Mutation*
  • RNA, Small Nucleolar/genetics*
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 32359472 Full text @ Am. J. Hum. Genet.
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.