Molecular Genetics of Noonan Syndrome and RASopathies.

Abstract

The RAS/MAPK signaling pathway plays an essential role in development and tumorigenesis by regulating cell proliferation, differentiation, apoptosis, migration, and metabolism. Therefore, it is not surprising that germline mutations in genes encoding components or regulators of this signaling pathway cause numerous human genetic conditions, including Noonan syndrome and related disorders. The term "RASopathies" has been used to describe these disorders collectively due to their common underlying RAS/MAPK pathway dysregulation and overlapping clinical features. Taken together, the RASopathies represent one of the most common groups of genetic disorders, affecting approximately 1 in 1,000 individuals. This review describes the RAS/MAPK signaling pathway, summarizes multiple molecular genetic approaches used during the last several decades to discover genes responsible for different RASopathies, and finally focuses on several major disease genes associated with Noonan syndrome and related disorders with regard to genomic locations, structure, mutations, and genotype-phenotype correlations.