{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Norppa AJ"],"funding":["Academy of Finland","Jane and Aatos Erkko Foundation","University of Helsinki","Sigrid Jusélius Foundation"],"pagination":["2835-2847"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7968993"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["49(5)"],"pubmed_abstract":["Disruption of minor spliceosome functions underlies several genetic diseases with mutations in the minor spliceosome-specific small nuclear RNAs (snRNAs) and proteins. Here, we define the molecular outcome of the U12 snRNA mutation (84C>U) resulting in an early-onset form of cerebellar ataxia. To understand the molecular consequences of the U12 snRNA mutation, we created cell lines harboring the 84C>T mutation in the U12 snRNA gene (RNU12). We show that the 84C>U mutation leads to accelerated decay of the snRNA, resulting in significantly reduced steady-state U12 snRNA levels. Additionally, the mutation leads to accumulation of 3'-truncated forms of U12 snRNA, which have undergone the cytoplasmic steps of snRNP biogenesis. Our data suggests that the 84C>U-mutant snRNA is targeted for decay following reimport into the nucleus, and that the U12 snRNA fragments are decay intermediates that result from the stalling of a 3'-to-5' exonuclease. Finally, we show that several other single-nucleotide variants in the 3' stem-loop of U12 snRNA that are segregating in the human population are also highly destabilizing. This suggests that the 3' stem-loop is important for the overall stability of the U12 snRNA and that additional disease-causing mutations are likely to exist in this region."],"journal":["Nucleic acids research"],"pubmed_title":["The integrity of the U12 snRNA 3' stem-loop is necessary for its overall stability."],"pmcid":["PMC7968993"],"funding_grant_id":["308657"],"pubmed_authors":["Norppa AJ","Frilander MJ"],"additional_accession":[]},"is_claimable":false,"name":"The integrity of the U12 snRNA 3' stem-loop is necessary for its overall stability.","description":"Disruption of minor spliceosome functions underlies several genetic diseases with mutations in the minor spliceosome-specific small nuclear RNAs (snRNAs) and proteins. Here, we define the molecular outcome of the U12 snRNA mutation (84C>U) resulting in an early-onset form of cerebellar ataxia. To understand the molecular consequences of the U12 snRNA mutation, we created cell lines harboring the 84C>T mutation in the U12 snRNA gene (RNU12). We show that the 84C>U mutation leads to accelerated decay of the snRNA, resulting in significantly reduced steady-state U12 snRNA levels. Additionally, the mutation leads to accumulation of 3'-truncated forms of U12 snRNA, which have undergone the cytoplasmic steps of snRNP biogenesis. Our data suggests that the 84C>U-mutant snRNA is targeted for decay following reimport into the nucleus, and that the U12 snRNA fragments are decay intermediates that result from the stalling of a 3'-to-5' exonuclease. Finally, we show that several other single-nucleotide variants in the 3' stem-loop of U12 snRNA that are segregating in the human population are also highly destabilizing. This suggests that the 3' stem-loop is important for the overall stability of the U12 snRNA and that additional disease-causing mutations are likely to exist in this region.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Mar","modification":"2025-04-05T14:55:13.126Z","creation":"2025-04-05T14:55:13.126Z"},"accession":"S-EPMC7968993","cross_references":{"pubmed":["33577674"],"doi":["10.1093/nar/gkab048"]}}