Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Academic Article uri icon

abstract

  • Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

published proceedings

  • Nat Genet

altmetric score

  • 19

author list (cited authors)

  • Tartaglia, M., Pennacchio, L. A., Zhao, C., Yadav, K. K., Fodale, V., Sarkozy, A., ... Gelb, B. D.

citation count

  • 472

complete list of authors

  • Tartaglia, Marco||Pennacchio, Len A||Zhao, Chen||Yadav, Kamlesh K||Fodale, Valentina||Sarkozy, Anna||Pandit, Bhaswati||Oishi, Kimihiko||Martinelli, Simone||Schackwitz, Wendy||Ustaszewska, Anna||Martin, Joel||Bristow, James||Carta, Claudio||Lepri, Francesca||Neri, Cinzia||Vasta, Isabella||Gibson, Kate||Curry, Cynthia J||Siguero, Juan Pedro L√≥pez||Digilio, Maria Cristina||Zampino, Giuseppe||Dallapiccola, Bruno||Bar-Sagi, Dafna||Gelb, Bruce D

publication date

  • January 2007