Functional Characterization of Genetic Variants in Rare Disease Associated with Shoc2 scaffold

Summary Mutations in the Shoc2 gene result in a developmental disorder called Noonan syndrome with loose anagen hair (NSLH), a condition affecting craniofacial features, the heart, the digestive system, and neural development. The Shoc2 is essential for transmitting the ERK1/2 cascade signals that control the morphogenesis of neural crest-derived tissues. Shoc2 forms intricate protein complexes to amplify intracellular signals, regulate the distribution of signaling proteins, and control gene expression programs during cell lineage specification. This application is led by the notion that functional analyses of different Shoc2 variants of unknown significance identified in patients with birth defects will give important insights into the mechanisms by which these pathogenic variants affect cell differentiation and how these alterations lead to the variety of phenotypes observed in NSLH patients. We will use a zebrafish vertebrate model carrying patient variants to gain insights into the molecular and cellular processes altered by Shoc2 variants in neural crest-derived lineages. This study will also examine how these variants impact Shoc2's function by dissecting its interactions with other proteins and its localization within cells using biochemical and biophysical approaches. Results from this work will fill an essential gap in our understanding of the fundamental principles by which alterations of different aspects of signal transmission result in human disease with variable phenotypic outcomes. This work will also have a broader impact on elucidating the importance of cell signaling mechanisms in craniofacial morphogenesis.