Mutation analysis of the genes involved in the Ras-mitogen-activated protein kinase (MAPK) pathway in Korean patients with Noonan syndrome.

Noonan syndrome (NS) is a congenital abnormality that affects multiple parts of the body. Approximately 50% of cases are caused by mutations in the PTPN11 gene. NS shares many clinical features with a group of developmental disorders including Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Recently, KRAS and SOS1 were identified as causative genes for NS. Moreover, mutations in several genes associated with the Ras-mitogen-activated protein kinase (MAPK) pathway, including HRAS, BRAF, MEK1, and MEK2 were identified in patients with Costello syndrome and CFC syndrome. Accordingly, this study carried out mutation analysis of nine genes including PTPN11, SOS1, GRB2, KRAS, HRAS, NRAS, BRAF, MEK1, and MEK2 associated with the Ras-MAPK pathway in 14 Korean patients with NS. Seven patients were found to have mutations in the PTPN11 gene. Mutation analyses of the other genes did not reveal any disease causing mutations except for one unclassified variation in the 3'-untranslated region of the HRAS gene (c.*1C>T). The patient's father also had the same substitution with the normal phenotype. Therefore, this variation is believed to be either a rare polymorphism or a disease-related variation with variable penetrance. The Ras-MAPK pathway has now emerged as a key cascade in a group of similar developmental disorders as well as in many types of cancers. This study found that, with the exception of PTPN11, mutations in genes related to the Ras-MAPK pathway appear to be uncommon, at least in Korean patients with NS.