A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis

Nic Robertson, Vadim Shchepachev, David Wright, Tomasz W. Turowski, Christos Spanos, Aleksandra Helwak, Rose Zamoyska, David Tollervey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article number649
Number of pages14
JournalNature Communications
Issue number1
Publication statusPublished - 3 Feb 2022


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