MOLECULAR BASES OF NOONAN SYNDROME AND RELATED DISORDERS

Noonan syndrome (NS) is the most common non-chromosomal syndrome with congenital heart disease. While cardiovascular involvement, which includes pulmonary valve stenosis and early-onset hypertrophic cardiomyopathy most commonly, is observed in 80-90% of individuals with this disorder, additional relatively frequent features are skeletal defects, short/webbed neck, developmental delay and cryptorchidism. NS is genetically heterogeneous, and three disease genes, PTPN11, KRAS and SOS1, which encode for transducers participating in RAS signaling, have been identified by the applicant and collaborators to this proposal. Mutations in these genes account for approximately 60% of individuals with NS, and cause enhanced RAS-mediated signal flow. Understanding the molecular causes of NS and related conditions is a requisite to diagnose and treat these disorders effectively. While the completed research on PTPN11 has provided insights into the molecular basis of disease, there are fundamental questions about disease pathogenesis that remain unanswered. Major goals of this research project are to define prevalence, diversity and clinical relevance of mutations affecting the SOS1 and KRAS genes, and to delineate the phenotypic diversity resulting from mutations affecting these genes and others coding for proteins with biological role in RAS signaling, and their association with specific developmental defects. These studies will also provide insights into the effects of mutations on protein function and will allow the identification of novel disease genes for these disorders.