Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

J Clin Invest. 2010 Dec;120(12):4353-65. doi: 10.1172/JCI43910.


Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%-15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated pheno-types, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Heart / embryology
  • Heterozygote
  • Homozygote
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Mutation*
  • Noonan Syndrome / embryology
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / metabolism
  • Phenotype
  • Pregnancy
  • SOS1 Protein / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • rac GTP-Binding Proteins / metabolism


  • SOS1 Protein
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • rac GTP-Binding Proteins