MOLECULAR BASES OF NOONAN SYNDROME AND RELATED DISORDERS

Noonan syndrome (NS) is the most common non-chromosomal syndrome with congenital heart disease. NS is genetically heterogeneous, and a major disease gene, PTPN11, which encodes the protein tyrosine phosphatase SHP-2, has been identified. PTPN11 is mutated in approximately 50% of individuals with NS. More recently, germ-line mutations in this gene have been documented in other developmental disorders that are clinically related to NS. Somatic PTPN11 mutations have been also documented in some hematologic malignancies. First experimental evidence supports that PTPN11 mutations promote SHP-2 gain-of-function. Understanding the molecular causes of NS and related disorders is a requisite to diagnose and treat these diseases effectively. Major goals of this research project are to define prevalence, distribution, and clinical and functional significance of PTPN11 mutations, and to identify novel NS disease genes. The proposed studies will delineate the different clinical conditions resulting from PTPN11 mutations, the type and distribution of mutations in the PTPN11 gene, and possible associations between mutations and specific developmental defects. The studies will also provide insights into the effects of mutations on protein function and data that will allow the identification of novel disease genes for these disorders.