[HTML][HTML] Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation
PC Chen, H Wakimoto, D Conner… - The Journal of …, 2010 - Am Soc Clin Investig
PC Chen, H Wakimoto, D Conner, T Araki, T Yuan, A Roberts, CE Seidman, R Bronson…
The Journal of clinical investigation, 2010•Am Soc Clin InvestigNoonan 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 …
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 …
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 phenotypes, 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.
The Journal of Clinical Investigation