Kiel, CristinaSerrano Pubull, Luis, 1982-2024-02-192024-02-192014Kiel C, Serrano L. Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations. Molecular Systems Biology. 2014 May;10(5):727. DOI: 10.1002/msb.201450921744-4292http://hdl.handle.net/10230/59139The Ras/MAPK syndromes (‘RASopathies’) are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen‐activated protein kinase (MAPK) pathway frequently involved in cancer. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either cancer or RASopathies. Here, we shed light on 956 RASopathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures. Using the protein design algorithm FoldX, we predict that most of the missense mutations with destabilising energies are in structural regions that control the activation of proteins, and only a few are predicted to compromise protein folding. We find a trend that energy changes are higher for cancer compared to RASopathy mutations. Through network modelling, we show that partly compensatory mutations in RASopathies result in only minor downstream pathway deregulation. In summary, we suggest that quantitative rather than qualitative network differences determine the phenotypic outcome of RASopathy compared to cancer mutations.application/pdfeng© 2014 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/msb.20145092RASopathyFoldXMAPK pathwayMissense mutationsEnedgeticsinfo:eu-repo/semantics/openAccess