Evaluating Causes for Failure to Thrive in a Noonan-like Syndrome with Loose Anagen Hair (NSLH) Patients using NSLH Vertebrate Model

Summary Even though the genetic basis of RASopathies has been acknowledged for more than a decade, the development of therapies that radically improve clinical outcomes for RASopathy patients has not rapidly progressed. Failure to thrive, gain weight, and grow are common symptoms of RASopathies, but the underlying causes of these symptoms are not known. Our lab is studying a RASopathy called Noonan syndrome with loose anagen hair (NSLAH), where patients suffer from delayed development of the gastrointestinal system and perturbations in metabolic pathways. In these studies, we will use zebrafish as a vertebrate model to investigate how mutations in the shoc2 gene, found in patients with NSLAH, affect the early stages of gastrointestinal development and metabolism. Zebrafish offer distinct advantages for development studies, including their transparency and rapid external development. Thus, determining how metabolic perturbations affect this clinically relevant model''s growth and developmental patterns will lead to better treatment for patients with NSLAH. These insights could identify oral supplements for patients, similar to what recently was identified for congenital disorders of glycosylation and neonatal hypoxia-ischemia patients. While this work focuses on a specific RASopathy, our findings will impact other RASopathies where patients present with similar difficulties to thrive. The proposed work will also establish a foundation for successful future studies focused on the development of specific strategies for therapeutic approaches in RASopathies.