A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis.
Springer Science and Business Media LLC
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Robertson, N., Shchepachev, V., Wright, D., Turowski, T. W., Spanos, C., Helwak, A., Zamoyska, R., & et al. (2022). A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-28295-8
RMRP encodes a non-coding RNA forming the core of the RNase MRP ribonucleoprotein complex. Mutations cause Cartilage Hair Hypoplasia (CHH), characterized by skeletal abnormalities and impaired T cell activation. Yeast RNase MRP cleaves a specific site in the pre-ribosomal RNA (pre-rRNA) during ribosome synthesis. CRISPR-mediated disruption of RMRP in human cells lines caused growth arrest, with pre-rRNA accumulation. Here, we analyzed disease-relevant primary cells, showing that mutations in RMRP impair mouse T cell activation and delay pre-rRNA processing. Patient-derived human fibroblasts with CHH-linked mutations showed similar pre-rRNA processing delay. Human cells engineered with the most common CHH mutation (70AG in RMRP) show specifically impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Moreover, the 70AG mutation caused a reduction in intact RNase MRP complexes. Together, these results indicate that CHH is a ribosomopathy.
T-Lymphocytes, Cells, Cultured, K562 Cells, Ribosomes, Fibroblasts, Hair, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Osteochondrodysplasias, Hirschsprung Disease, Endoribonucleases, RNA Precursors, RNA, Ribosomal, Cell Proliferation, Base Sequence, Mutation, RNA Folding, RNA, Long Noncoding, Primary Immunodeficiency Diseases
Wellcome Trust (077248, 210101, 203149, 205014, WT205014/Z/16/Z)
External DOI: https://doi.org/10.1038/s41467-022-28295-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334749
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/