摘要：

RASopathies are diseases that arise from germline mutations in the RAS/MAPK signaling pathway and affect 1 in 1000 live births. RASopathy patients display symptoms including congenital heart defects (CHD), short stature, craniofacial defects, and neurocognitive delay. Two of the most commonly occurring RASopathies are Noonan syndrome (NS) and Noonan Syndrome with multiple lentigines (NSML), which affect 1 in 1500 births and display typical RASopathy symptoms as well as an increased risk of developing cancer. 50% Noonan syndrome and 90% of NSML cases come from mutations in Src homology phosphatase 2 (SHP2), a protein found in the RAS pathway that can act as both an adaptor protein that recruits protein complexes to upregulate signaling, and as a phosphatase that dephosphorylates and inactivates proteins that downregulate signaling activity. Though mutations associated with both NS and NSML have been identified, there has not been a way to convert knowledge of these mutations into specific predictions of disease progression, and there is difficulty in assigning causation and severity of these mutations. In this study, I ranked mutant SHP2 variants for their impact on developmental events in zebrafish. Zebrafish are ideal candidates for modeling these disorders because the Ras/MAPK is a highly conserved pathway in all eukaryotes, methods of precisely genetically manipulating and altering protein levels have been established, and because zebrafish undergo external fertilization and have translucent embryos that makes it easy to observe developmental events. Results of this study show that SHP2 mutant expressing embryos display phenotypes mirroring the CHD, shortened stature, and craniofacial malformations in patients, that can be quantitatively ranked by severity. My mutations provide a methodology to efficiently predict the severity of new mutations and may provide insight into patient-specific disease progression.

展开