1. A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis
- Author
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Nic Robertson, Vadim Shchepachev, David Wright, Tomasz W. Turowski, Christos Spanos, Aleksandra Helwak, Rose Zamoyska, David Tollervey, Shchepachev, Vadim [0000-0001-8551-5940], Turowski, Tomasz W [0000-0002-7052-8682], Spanos, Christos [0000-0002-4376-8242], Zamoyska, Rose [0000-0001-9816-2638], Tollervey, David [0000-0003-2894-2772], and Apollo - University of Cambridge Repository
- Subjects
RNA Folding ,Ribosomopathy ,T-Lymphocytes ,General Physics and Astronomy ,13 ,medicine.disease_cause ,Ribosome ,RNA Precursors ,42/41 ,Mitochondrial ribosome ,Cells, Cultured ,Mice, Knockout ,Mutation ,Multidisciplinary ,Chemistry ,article ,Cell biology ,13/31 ,631/337/384/2568 ,RNA, Long Noncoding ,631/80/304 ,Primary Immunodeficiency Diseases ,Science ,631/250/2502 ,38/90 ,13/106 ,Osteochondrodysplasias ,General Biochemistry, Genetics and Molecular Biology ,38 ,38/91 ,Endoribonucleases ,631/208/200 ,medicine ,Animals ,Humans ,Hirschsprung Disease ,RRNA processing ,Gene ,Cell Proliferation ,Base Sequence ,82/58 ,RNA ,General Chemistry ,Fibroblasts ,49 ,Mice, Inbred C57BL ,RNase MRP ,RNA, Ribosomal ,631/1647/2017/2003 ,K562 Cells ,Ribosomes ,Hair - Abstract
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, and the first processing-specific human disorder to be described.HighlightsMutations in RMRP lncRNA impair pre-rRNA processing and T cell activationPatient derived fibroblasts show impaired pre-rRNA processingCells with the most common disease-linked mutation have specific processing defectsCytoplasmic ribosomes and intact RNase MRP complexes are also reduced in these cells
- Published
- 2021