Dysregulated RNA modifications in the context of human development

Key Words: Gene expression regulation, RNA methylation, Intellectual disability

Rapid advances in genome sequencing have revealed the genetic changes that cause many types of developmental delays and disorders. Uncovering the molecular mechanisms that drive these changes, however, has been a challenge, and requires approaches specific to the mutated gene and/or protein in question. Ribosomopathies are a class of diseases that stem from defects in the ribosome, a large molecular machine that is responsible for producing protein in the cell. Despite the fact that ribosomes are ubiquitously required for cell growth and function, different ribosomopathies manifest with tissue-specific symptoms, and we have a very limited understanding of why this is the case. This work is focused on a protein factor called METTL5, which installs a regulatory chemical modification to one of the RNA components of the ribosome, and until recently we had very little understanding of the molecular mechanism of METTL5 function. Mutations in METTL5 have previously been shown to cause intellectual disability, microcephaly, and other developmental defects, but these studies were performed prior to our and others’ recent work on METTL5. We will apply the tools we have developed to study the function of METTL5 protein towards understanding why the mutations found in patients are so disruptive. By revealing the molecular mechanisms that behind these processes, we hope to reveal therapeutic avenues that may help improve quality of life.