Germline KRAS mutations cause Noonan syndrome

Abstract

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

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

“…Phenotypically overlapping Costelo syndrome and cardio-facio-cutaneous syndrome are caused by gain-of-function HRAS mutation and KRAS/BRAF/MEK1/MEK2 mutation, respectively (Aoki et al, 2005;Niihori et al, 2006;RodriguezViciana et al, 2006). Some Noonan syndrome cases are also attributed to gain-of-function mutations in SOS1 that encodes the RAS guanine nucleotide exchange factor or KRAS (Schubbert et al, 2006;Roberts et al, 2007;Tartaglia et al, 2007). The observations collectively indicate that aberrant activation of the SHP-2-RAS-ERK pathway plays a key role in these overlapping developmental disorders (Gelb and Tartaglia, 2006).…”

Differential Regulation of RasGAPs in Cancer

“…[16][17][18][19] Along these lines, defects in human development have recently been associated with Ras isoform-specific functions. [19][20][21] The different magnitude of oncogenic Ras isoform signaling further supports signal specificity of Ras isoforms. Although there is some controversy about the differential ability of Ras isoforms to activate downstream effectors, some studies suggested that H-Ras strongly activates the PI3K/Akt pathway, while K-Ras is a more potent activator of the Raf/MAPK pathway.…”

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

“…These disorders share similar phenotypic features including: short stature, short neck, cardiovascular defects, facial anomalies, learning difficulties and predisposition to developing cancers. Genetic screening of patients with Noonan syndrome has identified gain of function mutations in PTPN11 (50%), Sos1 (20%) and K-Ras (5%) [12][13][14][15]. H-Ras is mutated in >85% of Costello syndrome cases and K-Ras (7%), B-Raf (>35%), MEK (13%) are mutated in CFC syndrome [16][17][18].…”