Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

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

Research output: Contribution to journalArticlepeer-review


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 syndromeĝ€"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.

Original languageEnglish
Pages (from-to)75-79
Number of pages5
JournalNature Genetics
Issue number1
Publication statusPublished - Jan 2007

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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