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

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.