Germline gain-of-function mutations in SOS1 cause Noonan syndrome

Abstract

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

“…The analysis of SOS1 illustrates the individualized approach for each syndrome and mutation. Since Roberts et al [2007] listed each patient allowing complete analysis, and Zenker et al [2007b] provided a summary table useful for many data points, both references were used in a complementary fashion; a smaller series [Narumi et al, 2008] was omitted as per general methods. A condensed comparison is shown in Table VI based on study patient data only.…”

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 allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family

“…17 We here show that the SOS1 c. M269R)) changes in exon 6 have been shown to be pathogenetic mutations. 13 The three affected members of the NS family here described did not show any mutation in the known NS genes other than the c.755T4C SOS1 variant. Our proband's phenotype resembles that of SOS1-mutated individuals, being associated with relative macrocephaly, ptosis and absence of short stature, whereas her cutaneous findings -lentigines, cafè-au-lait spots -are similar to those of NS-like with lentigines rather than those found in Cardio-facio-cutaneous syndrome and patients with SOS1 gene mutations, 8 that is, hyperkeratotic skin, sparse eyebrows, sparse slow growing curly hair.…”

“…At this purpose we transfected HEK293 cells with the mutant Sos-p.I252T plasmid, the wild-type human SOS1 or the mutant isoform SOS1 c.806T 4 C (p.(M269R)), previously reported to activate the RAS-ERK pathway 13 as a positive control and compared the ERK1 phosphorylation levels of each SOS1 isoform before and after EGF stimulation. We found that the Sos-p.I252T substitution significantly increased ERK1 phosphorylation level, with a level comparable to the c.806T 4 C (p.(M269R)) mutant-positive control (Figure 2a and b).…”