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

Abstract

Mutations in the human RMRP gene cause Cartilage Hair Hypoplasia (CHH), an autosomal recessive disorder characterized by skeletal abnormalities and impaired T cell activation. RMRP encodes a non-coding RNA, which forms the core of the RNase MRP ribonucleoprotein complex. In budding yeast, RMRP 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. Analysis of pre-rRNA processing in patient-derived human fibroblasts with CHH-linked mutations showed a similar pattern of 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 human disorder of rRNA processing to be described.

Essential Role of Translation Factor eIF5a in Cytokine Production and Cell Cycle Regulation in Primary CD8 T Lymphocytes

“…In this case some of the more global downregulation of translation may not be linked to the elongation activity of eIF5a directly but rather indirectly through its influence on ribosomal protein translation. Interestingly in this context is a recent description of a ribosomopathy that presents as immune deficiency and impaired T cell activation (Robertson et al, 2021), providing further evidence that successful CD8 T cell activation may be particularly sensitive to ribosome composition.…”

Essential role of translation factor eIF5a in cytokine production and cell cycle regulation in primary CD8 T lymphocytes

“…In this case some of the more global downregulation of translation may not be linked to the elongation activity of eIF5a directly but rather indirectly through its influence on ribosomal protein translation. Interestingly in this context is a recent description of a ribosomopathy that presents as immune deficiency and impaired T cell activation (Robertson et al, 2021), providing further evidence that successful T cell activation may be particularly sensitive to ribosome composition.…”