The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

Cordeddu, V., Yin, J. C., Gunnarsson, C., Virtanen, C., Drunat, S., Lepri, F., De Luca, A., Rossi, C., Ciolfi, A., Pugh, T. J., Bruselles, A., Priest, J. R., Pennacchio, L. A., Lu, Z., Danesh, A., Quevedo, R., Hamid, A., Martinelli, S., Pantaleoni, F., Gnazzo, M., Daniele, P., Lissewski, C., Bocchinfuso, G., Stella, L., Odent, S., Philip, N., Faivre, L., Vlckova, M., Seemanova, E., Digilio, C., Zenker, M., Zampino, G., Verloes, A., Dallapiccola, B., Roberts, A. E., Cave, H., Gelb, B. D., Neel, B. G., Tartaglia, M., Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome, <<HUMAN MUTATION>>, 2015; 36 (11): 1080-1087. [doi:10.1002/humu.22834] [http://hdl.handle.net/10807/172622]

Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome

Zampino, Giuseppe;
2015

Abstract

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.
2015
Inglese
Cordeddu, V., Yin, J. C., Gunnarsson, C., Virtanen, C., Drunat, S., Lepri, F., De Luca, A., Rossi, C., Ciolfi, A., Pugh, T. J., Bruselles, A., Priest, J. R., Pennacchio, L. A., Lu, Z., Danesh, A., Quevedo, R., Hamid, A., Martinelli, S., Pantaleoni, F., Gnazzo, M., Daniele, P., Lissewski, C., Bocchinfuso, G., Stella, L., Odent, S., Philip, N., Faivre, L., Vlckova, M., Seemanova, E., Digilio, C., Zenker, M., Zampino, G., Verloes, A., Dallapiccola, B., Roberts, A. E., Cave, H., Gelb, B. D., Neel, B. G., Tartaglia, M., Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome, <<HUMAN MUTATION>>, 2015; 36 (11): 1080-1087. [doi:10.1002/humu.22834] [http://hdl.handle.net/10807/172622]
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