Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Abstract

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

“…The exons and flanking introns of ANGPTL4 were sequenced in both directions in 3,551 participants in the Dallas Heart Study as described 21 . The oligonucleotide primers used for sequencing are shown in Supplementary Table 1.…”

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

“…Primer sequences are published elsewhere. 10,11 PCR was carried out in a 50 μl reaction volume containing 150 ng of genomic DNA, 0.2 μM primers, 100 μM dNTPs, 10 × reaction buffer, 50 mM MgCl 2 and 2.5 U GoTaq DNA Polymerase (Promega, Madison, WI, USA) with the following cycling profile: 4 min initial denaturation at 95°C, 35 cycles as follows: 95°C for 30 s, 55°C for 30 s and 72°C for 30 s.…”

“…9 Many affected adults are diagnosed only after the birth of a more obviously affected infant, and in fact milder or subclinical phenotypes have been reported in PTPN11 and SOS1 mutation carriers. 10,11 The reported different degrees of severity of NS phenotype in both familial and sporadic carriers, for the same or similar functional mutations, are suggestive of the involvement of cis/trans regulatory factors, modulating the effects of specific mutations that should be investigated.…”