The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Abstract

The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of the cell cycle, differentiation, growth and cell senescence, all of which are critical to normal development. It is therefore not surprising that its dysregulation has profound effects on development. A class of developmental syndromes, the 'RASopathies', is caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway. The vast majority of these mutations result in increased signal transduction down the Ras/MAPK pathway, but usually to a lesser extent than somatic mutations associated with oncogenesis. Each syndrome exhibits unique phenotypic features, however, since they all cause dysregulation of the Ras/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes, including characteristic facial features, cardiac defects, cutaneous abnormalities, neurocognitive delay and a predisposition to malignancies. Here we review the clinical and underlying molecular basis for each of these syndromes.

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Figure 1

The Ras/mitogen-activated protein kinase (MAPK) signaling pathway and associated developmental syndromes (indicated by dashed lines). The MAPK signaling pathway of protein kinases is critically involved in cell proliferation, differentiation, motility, apoptosis and senescence. The Ras/MAPK pathway proteins with germline mutations in their respective genes are associated with Noonan, LEOPARD, gingival fibromatosis 1, neurofibromatosis 1, capillary malformation-arteriovenous malformation, Costello, autoimmune lymphoproliferative (ALPS), cardio-facio-cutaneous and Legius syndromes.