Defining the molecular pathogenesis of the ribosomopathy cartilage hair hypoplasia - Telethon Exploratory Grant GEP 15019

Cartilage Hair Hypoplasia (CHH) is a rare autosomal recessive disorder due to RMRP gene mutations, characterized by meta-epiphyseal osteochondrodysplasia leading to severe skeletal abnormalities. RMRP gene encodes for the RNA component of mitochondrial RNA-processing endoribonuclease, an enzyme involved in ribosomal RNA processing. CHH is therefore classified as a ribosomopathy. The molecular pathogenesis of CHH is far from being defined, leading to the need for a detailed study of the effects of CHH-related alterations on rRNA processing and other the cellular processes where RMRP is involved. At present, the mechanisms being considered responsible for the pathogenesis of ribosomopathies involve either the production of altered ribosomes, causing quantitative and qualitative alterations in proteins’ translation, or the activation of the so called ribosomal stress response, leading to a p53 dependent growth arrest and apoptosis. To study the molecular and cellular features of cells bearing altered RMRP function, we plan to decrease RMRP expression to different extents in cultured primary human chondrocytes. In these cellular models we aim to evaluate in detail cell behavior, ribosome biogenesis, ribosomal stress response and translational regulation of gene expression after RMRP depletion. This strategy will allow us to provide new insights into the molecular processes leading to CHH-associated skeletal defects, thereby paving the way to future studies aimed to explore so far unconsidered therapeutic approaches.