Developmental Syndromes of Ras/ MAPK Pathway Dysregulation

Abstract

Abstract The term RASopathies designates a group of developmental syndromes caused by germline mutations in genes that encode proteins of the Ras/mitogen‐activated protein kinase (MAPK) signalling pathway. Ras/MAPK pathway controls several biological functions, such as cell proliferation, migration, differentiation and apoptosis. Similar molecular mechanisms disturbing the Ras/MAPK pathway were described in the RASopathies, including Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome‐like disorder with loose anagen hair, CBL mutation‐associated syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and Legius syndrome. Even though these syndromes share some overlapping features, genotype–phenotype correlations are well established for each of these, supporting the idea that they represent clinically distinct disorders. Owing to the similar mechanism encompassing Ras/MAPK germline and somatic mutations, Ras/MAPK pathway components have been considered a potential therapeutic target for RASopathies by promoting pathway modulation or small‐molecule inhibition. Key Concepts: Ras/MAPK is one of the most well‐known signalling pathways and plays an important role in critical cellular functions to normal development. RASopathies are a group of medical genetic disorders caused by gain‐of‐function germline mutations in components of the Ras/MAPK signalling pathway. Although the RASopathies may share clinically overlapping features, they also exhibit some individual ones that support the concept that they are distinct disorders. Ras/MAPK germline mutations are similar to somatic mutations when associated with cancer, but they tend to be weakly activating. Noonan syndrome is a frequent autosomal dominant disorder characterised by facial dysmorphisms, heart defects, short stature and learning disabilities. The best clinical practice for each RASopathy could be defined if its genotype–phenotype correlation is understood.