SOS1 Mutations Research Articles

Genetics of Noonan syndrome - a new gene, and the search is still on

Germline gain-of-function mutations in SOS1 cause Noonan syndromeRoberts et al. (2007)Nature Genetics 39: 70–74 Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndromeTartaglia et al. (2007)Nature Genetics 39: 75–79

Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome

Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was...

Germ Line Gain of Function with SOS1 Mutation in Hereditary Gingival Fibromatosis

Mutation of human SOS1 is responsible for hereditary gingival fibromatosis type 1, a benign overgrowth condition of the gingiva. Here, we investigated molecular mechanisms responsible for the increased rate of cell proliferation in gingival fibroblasts caused by mutant SOS1 in vitro. Using ectopic expression of wild-type and mutant SOS1 constructs, we found that truncated SOS1 could localize to the plasma membrane, without growth factor stimuli, leading to sustained activation of Ras/MAPK signaling. Additionally, we observed an increase in the magnitude and duration of ERK signaling in hereditary gingival fibromatosis gingival fibroblasts that was associated with phosphorylation of retinoblastoma tumor suppressor protein and the up-regulation of cell cycle regulators, including cyclins C, D, and E and the E2F/DP transcription factors. These factors promote cell cycle progression from G(1) to S phase, and their up-regulation may underlie the increased gingival fibroblast proliferation observed. Selective depletion of wild-type and mutant SOS1 through small interfering RNA demonstrates the link between mutation of SOS1, ERK signaling, cell proliferation rate, and the expression levels of Egr-1 and proliferating cell nuclear antigen. These findings elucidate the mechanisms for gingival overgrowth mediated by SOS1 gene mutation in humans.

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.

Sending out an SOS

Noonan syndrome is a disease caused by aberrant signaling through the Ras GTPase, yet the underlying causal mutations remain unknown in many affected individuals. Two papers now identify gain-of-function mutations in the Ras nucleotide exchange factor SOS1 as a new player in this common developmental disorder.

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

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.

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

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.

Salinity-induced ion flux patterns from the excised roots of Arabidopsis sos mutants

The SOS signal-transduction pathway is known to be important for ion homeostasis and salt tolerance in plants. However, there is a lack of in planta electrophysiological data about how the changes in signalling and ion transport activity are integrated at the cellular and tissue level. In this study, using the non-invasive ion flux MIFE technique, we compared net K+, H+ and Na+ fluxes from elongation and mature root zones of Arabidopsis wild type Columbia and sos mutants. Our results can be summarised as follows: (1) SOS mutations affect the function of the entire root, not just the root apex; (2) SOS signalling pathway is highly branched; (3) Na+ effects on SOS1 may by-pass the SOS2/SOS3 complex in the root apex; (4) SOS mutation affects H+ transport even in the absence of salt stress; (5) SOS1 mutation affects intracellular K+ homeostasis with a plasma membrane depolarisation-activated outward-rectifying K+ channel being a likely target; (6) H+ pump also may be a target of SOS signalling. We provide an improved model of SOS signalling and discuss physiological mechanisms underlying salt stress perception and signalling in plants. Our work shows that in planta studies are essential for understanding the functional genomics of plant salt tolerance.

Reduced Na+ uptake in the NaCl-hypersensitive sos1 mutant of Arabidopsis thaliana.

Sos1 is an Arabidopsis thaliana mutant with > 20 times higher sensitivity toward Na+ inhibition due to a defective high-affinity potassium-uptake system. We report here that sos1 accumulates less Na+ than the wild type in response to NaCl stress. The Na+ contents in sos1 seedlings exposed to 25 mM NaCl for 2 or more d are about 43% lower than those in the wild type. When assayed at 20 mM external NaCl, sos1 seedlings pretreated with low potassium have 32% lower Na+ uptake than the wild type. However, little difference in Na+ uptake could be measured when the seedlings were not pretreated with low potassium. Low-potassium treatment was shown to induce high-affinity potassium-uptake activity in Arabidopsis seedlings. No substantial difference in Na+ efflux between sos1 and the wild type was detected. The results show that the reduced Na+ accumulation in sos1 is due to a lower Na+ influx rate. Therefore, the sos1 mutation appears to disrupt low-affinity Na+ uptake in addition to its impairment of high-affinity K+ uptake.

Assignment of a Locus (GLC3A) for Primary Congenital Glaucoma (Buphthalmos) to 2p21 and Evidence for Genetic Heterogeneity

Primary congenital glaucoma (GLC3) is an inherited eye disorder that accounts for 0.01–0.04% of total blindness. Although a large number of chromosomal abnormalities have already been reported in patients with congenital glaucoma, the precise location and pathogenesis of this condition remain elusive. By using a group of 17 GLC3 families and a combination of both candidate regional and general positional mapping strategies, we have mapped a locus for GLC3 to the short arm of chromosome 2. Eleven families showed no recombination with 3 tightly linked markers of D2S177 (Z= 9.40), D2S1346 (Z= 8.83), and D2S1348 (Z= 8.90) with a combined haplotype lod score of 11.50. Haplotype and multipoint linkage analyses of 14 DNA markers from 2p indicated that the disease gene is located in the 2p21 region and is flanked by DNA markers D2S1788/D2S1325 (θ = 0.03;Z= 5.42) and D2S1356 (θ = 0.05;Z= 4.69). Inspection of haplotype and heterogeneity analysis confirmed that 6 families are not linked to the 2p21 region, thus providing the first proof of genetic heterogeneity for this phenotype. We therefore designated the locus on 2p21 GLC3A and positioned it in the overall linkage map of Tel– D 2 S 4 0 5 – D 2 S 3 6 7 – ( D 2 S 1 7 8 8 / D 2 S 1 3 2 5 ) – [ ( G L C 3 A , D 2 S 1 7 7 ) / ( D 2 S 1 3 4 6 / D 2 S 1 3 4 8 ) ] – D 2 S 1 3 5 6 – D 2 S 1 1 9 – D 2 S- [nb1761–D2S1248–D2S1352–D2S406–D2S441–Cen. Of the seven genes mapping to the 2p21 region, CAD, CALM2, and LHCGR are centromeric to D2S119 and can be excluded as a candidate for GLC3A, but mutations in PRKR, TIK, SOS1, or SPTBN1 may still be accountable for this phenotype. As human 2p21 shows homology with mouse chromosomes 11 and 17, the homolog of GLC3A is expected to reside on one of these two chromosomes.