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

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• The RMRP gene encodes a non-coding RNA crucial for the RNase MRP complex.
• Mutations in RMRP cause Cartilage Hair Hypoplasia (CHH), a disorder with skeletal issues and immune deficiencies.
• RNase MRP is essential for ribosome biogenesis, specifically pre-ribosomal RNA (pre-rRNA) processing.

Purpose of the Study:

• To investigate the functional consequences of RMRP mutations in primary cells.
• To determine if CHH is a ribosomopathy by analyzing ribosome biogenesis defects.

Main Methods:

• Analysis of primary mouse and human cells with RMRP mutations.
• CRISPR-mediated gene disruption in human cell lines.
• Assessment of pre-rRNA processing, rRNA maturation, and ribosome composition.

Main Results:

• RMRP mutations impair mouse T cell activation and delay pre-rRNA processing in primary cells.
• CHH patient-derived fibroblasts exhibit similar pre-rRNA processing delays.
• The common 70AG RMRP mutation specifically impairs pre-rRNA processing, reducing mature rRNA and altering cytosolic to mitochondrial ribosome ratios.

Conclusions:

• CHH is characterized by impaired ribosome biogenesis, classifying it as a ribosomopathy.
• RMRP mutations directly impact the integrity and function of the RNase MRP complex.
• Defective ribosome synthesis contributes to the cellular and developmental abnormalities seen in CHH.