Germline KRAS mutations cause Noonan syndrome

摘要: Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS that introduce V14I, T58I or D153V amino acid substitutions five individuals with a P34R alteration individual cardio-facio-cutaneous 115150), has overlapping features Recombinant V14I K-Ras proteins show defective intrinsic GTP hydrolysis impaired responsiveness GTPase activating proteins, render primary hematopoietic progenitors hypersensitive growth factors deregulate signal transduction cell lineage-specific manner. These studies establish as human disease infer the constellation developmental abnormalities seen spectrum is, large part, due hyperactive