The RASopathies: Syndromes of Ras/MAPK pathway dysregulation

Abstract

A class of clinically related developmental disorders, the RASopathies, has recently been shown to be caused by germline mutations in genes that encode components, or regulators, of the Ras/mitogen-activated protein kinase (MAPK) pathway. Neurofibromatosis type 1, the first syndrome identified to be caused by a germline mutation in this pathway, was followed by other syndromes including Noonan, Noonan with multiple lentigines, capillary malformation-AV malformation, Costello, cardio-facio-cutaneous, and Legius. The Ras/MAPK pathway plays an essential role in the regulation of the cell cycle, differentiation, growth, and cell senescence, all of which are critical to normal development. As a result, Ras/MAPK pathway dysregulation has been shown to have profound deleterious effects on both embryonic and later stages of development. Because the underlying molecular mechanism for these syndromes is dysregulation of the Ras/MAPK pathway, the RASopathies exhibit numerous overlapping phenotypic features, including reduced growth, characteristic facial features, cardiac defects, cutaneous abnormalities, neurocognitive delay, and a predisposition to neoplasia, both benign and malignant. As a group, the RASopathies are one of the largest recognizable patterns of malformation syndromes known, affecting approximately 1:1,000 individuals.