Alternative titles; symbols
HGNC Approved Gene Symbol: SOS1
Cytogenetic location: 2p22.1 Genomic coordinates (GRCh38): 2:38,981,549-39,124,868 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p22.1 | ?Fibromatosis, gingival, 1 | 135300 | Autosomal dominant | 3 |
| Noonan syndrome 4 | 610733 | Autosomal dominant | 3 |
RAS genes (e.g., 190020) encode membrane-bound guanine nucleotide-binding proteins that function in the transduction of signals that control cell growth and differentiation. Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins. GTP binding can be catalyzed by guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by GTPase-activating proteins (GAPs). The first exchange factor to be identified for RAS was the S. cerevisiae CDC25 gene product. Genetic analysis indicated that CDC25 is essential for activation of RAS proteins. In Drosophila, the protein encoded by the 'son of sevenless' gene (Sos) contains a domain that shows sequence similarity with the catalytic domain of CDC25. Sos may act as a positive regulator of RAS by promoting guanine nucleotide exchange.
Bowtell et al. (1992) isolated 2 cDNAs, designated Sos1 and Sos2 (601247), from a mouse eye library by screening with a probe from the Drosophila Sos gene. Sos1 encodes a predicted 1,336-amino acid protein which is 67% identical to the partial Sos2 sequence. Both Sos1 and Sos2 have an overall amino acid identity of 45% with the Drosophila Sos gene product. Northern blots showed that both genes are expressed in a wide variety of tissues and cell lines.
Chardin et al. (1993) isolated a human cDNA that encodes a widely expressed 1,333-amino acid protein that is closely related to the product of the Drosophila Sos gene and nearly identical to the mouse Sos1 gene product. A fragment of the human gene encoding the CDC25-related domain complemented loss of CDC25 function in yeast. The same domain of the human gene specifically stimulated guanine nucleotide exchange on mammalian RAS proteins in vitro. This and other evidence indicated to Chardin et al. (1993) that SOS1 is a guanine nucleotide exchange factor for RAS in the human. Further studies suggested that the coupling of receptor tyrosine kinases to RAS signaling is mediated by a molecular complex consisting of growth factor receptor-bound protein-2 (108355) and SOS1.
Hart et al. (2002) determined that the SOS1 gene spans 136 kb and consists of 24 exons. Intronic sizes range from 30 bp to 53 kb. The translation initiation codon is located at nucleotides 45 to 47 of exon 2, and the open reading frame is terminated at nucleotide 492 in exon 24.
Webb et al. (1993) mapped the mouse Sos1 gene to chromosome 17E by interspecific backcross analysis and in situ hybridization. They mapped the human SOS1 gene to chromosome 2p22-p21 by in situ hybridization.
Scita et al. (1999) showed that EPS8 (600206), E3B1 (603050), and SOS1 form a tricomplex in vivo that exhibits RAC (see 602048)-specific guanine nucleotide exchange factor (GEF) activity in vitro.
Epidermal growth factor receptor (EGFR; 131550) is required for skin development and is implicated in epithelial tumor formation. Sibilia et al. (2000) found that transgenic mice expressing SOS-F (a dominant form of SOS1 lacking the C-terminal region containing the GRB2-binding site and instead carrying the c-Ha-ras farnesylation site, which provides constitutive activity) driven by the keratin-5 (K5, or KRT5; 148040) promoter in basal keratinocytes developed skin papillomas with 100% penetrance. Tumor formation was inhibited, however, in mice with a hypomorphic (waved-2, or wa2, mice) and null Egfr background. Similarly, Egfr-deficient fibroblasts were resistant to transformation by SOS-F and rasV12, although tumorigenicity could be restored by expression of the antiapoptotic Bcl2 gene (151430). The K5-SOS-F papillomas and primary keratinocytes from wa2 mice displayed increased apoptosis and reduced Akt (164730) phosphorylation, and grafting experiments implied a cell-autonomous requirement for Egfr in keratinocytes. The authors concluded that EGFR provides an essential survival signal for SOS-dependent skin tumor development.
Huang et al. (2019) observed a multistep activation process for SOS which they suggested could, in principle, lead to longer-dwelling molecules having disproportionately higher activation rates, and showed that SOS activity is capable of being modulated by a kinetic proofreading mechanism. SOS is a key RAS activator that is autoinhibited in the cytosol and activates upon membrane recruitment. Autoinhibition release involves structural rearrangements of the protein at the membrane and thus introduces a delay between initial recruitment and activation. Huang et al. (2019) designed a single-molecule assay to resolve the time between initial receptor-mediated membrane recruitment and the initiation of GEF activity of individual SOS molecules on microarrays of RAS-functionalized supported membranes. The rise-and-fall shape of the measured SOS activation time distribution and the long mean time scale to activation (approximately 50 seconds) established a basis for kinetic proofreading in the receptor-mediated activation of RAS. Huang et al. (2019) further demonstrated that this kinetic proofreading is modulated by the LAT (602354)-GRB2 (108355)-SOS phosphotyrosine-driven phase transition at the membrane.
Proteins containing Dbl homology (DH) domains, such as SOS1, activate Rho family GTPases by functioning as specific guanine nucleotide exchange factors. All known DH domains have associated C-terminal pleckstrin homology (PH) domains that are implicated in targeting and regulatory functions. Soisson et al. (1998) determined the crystal structure of a fragment of the human SOS1 protein containing the DH and PH domains at 2.3 angstrom resolution. The entirely alpha-helical DH domain was unrelated in architecture to other nucleotide exchange factors. The active site of the DH domain, identified on the basis of sequence conservation and structural features, lies near the interface between the DH and PH domains. The structure suggested to the authors that ligation of the PH domain will be coupled structurally to the GTPase-binding site.
Gingival Fibromatosis 1
To identify the gene responsible for autosomal dominant gingival fibromatosis (GINGF1; 135300) mapped to chromosome 2p21, Hart et al. (2002) extended genetic linkage studies to refine the candidate interval; 16 genes were identified. Sequencing of these genes identified a mutation (182530.0001) in the SOS1 gene in affected individuals of 1 family. A transgenic mouse construct with a comparable SOS1 mutation was found to produce a phenotype with skin hypertrophy (Sibilia et al., 2000).
Noonan Syndrome 4
Noonan syndrome (see NS4; 610733) is a developmental disorder characterized by short stature, facial dysmorphism, congenital heart defects, and skeletal anomalies. Gain-of-function mutations in PTPN11 (176876), which encodes the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. Mutations in KRAS (190070) cause less than 5% of Noonan syndrome cases. Both SHP2 and KRAS participate in signaling through the RAS GTPase. Roberts et al. (2007) and Tartaglia et al. (2007) identified mutations in SOS1, which encodes an essential RAS guanine nucleotide exchange factor (GEF), in Noonan syndrome patients. Among patients with Noonan syndrome without mutation in PTPN11 or KRAS, Roberts et al. (2007) found missense SOS1 mutations in approximately 20%; Tartaglia et al. (2007), in 22 of 129 such individuals.
Noonan syndrome shares some phenotypic features with cardiofaciocutaneous syndrome (CFCS; 115150). Furthermore, both are due to heterozygous gain-of-function mutations in genes encoding proteins of the Ras-MAPK signaling cascade. Zenker et al. (2007) investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF (164757), MEK1 (176872), and MEK2 (601263). Missense mutations of SOS1 were discovered in 28% of patients with Noonan syndrome, thus confirming SOS1 as the second major gene for that disorder. In contrast, none of the patients classified as having CFCS carried a pathogenic sequence change in the SOS1 gene. Patients with NS and mutations in SOS1 (NS4; 610733) have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. Findings corroborated that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.
In 10 affected members of a 3-generation family segregating NS4, van Trier et al. (2017) identified a heterozygous missense mutation (P1045R; 182530.0007) in the SOS1 gene. The mutation was identified in the proband (patient IV-8) by next-generation sequencing of an NS gene panel and in additional family members by Sanger sequencing. No other pathogenic mutations or variants of uncertain significance were identified, and the mutation segregated with the disorder in the family. There was a range of clinical expression among the 10 family members from almost no NS4 characteristics to a typical presentation. The family was part of an NS cohort previously studied by van Trier et al. (2015).
In an extensive Brazilian family with hereditary gingival fibromatosis (GINGF1; 135300), Hart et al. (2002) demonstrated that the disorder was caused by insertion of a cytosine between nucleotides 126142 and 126143 in codon 1083 of the SOS1 gene. The insertion mutation introduced a frameshift and created a premature stop codon, abolishing 4 functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein. In the cDNA sequence, the insertion was between nucleotides 3248 and 3249. The mutation yielded a chimeric 1,105-amino acid protein that consisted of 1,083 SOS1 N-terminal amino acids in a normal sequence, followed by 22 replaced amino acids and a premature stop codon at codon 1106.
In a 6-year-old girl with sporadic Noonan syndrome (NS4; 610733), Roberts et al. (2007) found a 797C-A transversion in exon 6 of the SOS1 gene that resulted in a thr266-to-lys substitution (T266K). The child had hypertrophic cardiomyopathy with thrombocytopenia and easy bruising.
Ferrero et al. (2008) reported a newborn with Noonan syndrome and the T266K mutation. The pregnancy was characterized by polyhydramnios and increased fetal nuchal translucency. Dysmorphic facial features included hypertelorism, epicanthal folds, flat nasal bridge, low-set posteriorly rotated ears, and short neck. Other features included moderate pulmonic stenosis and bilateral cryptorchidism. Developmental milestones were normal at 24 months of age. There were no coagulation abnormalities. Ferrero et al. (2008) noted the phenotypic differences from the patient reported by Roberts et al. (2007).
In 2 patients with sporadic Noonan syndrome (NS4; 610733), Roberts et al. (2007) detected an 806T-G transversion in the SOS1 gene that caused a met269-to-arg (M269R) substitution. One of the patients was a 7-year-old boy with pulmonic stenosis and hypertrophic cardiomyopathy, easy bruising, and cryptorchidism with inguinal hernia. The other was an 11-year-old boy with pulmonic stenosis and atrial septal defect and cryptorchidism. School placement was regular in both cases. Tartaglia et al. (2007) identified the same mutation in 1 patient, also a sporadic case.
In a 41-year-old father and his infant son, Roberts et al. (2007) found that Noonan syndrome (NS4; 610733) was associated with a missense mutation in the SOS1 gene: an arg552-to-gly substitution (R552G) caused by a 1654A-G transition. The son had pulmonic stenosis. The father had cryptorchidism. Both showed 25 to 50% normal linear growth. Tartaglia et al. (2007) identified this mutation in 2 de novo cases.
In a girl with Noonan syndrome-4 (NS4; 610733) who had pigmented villonodular synovitis (PVNS), Mascheroni et al. (2008) identified a de novo heterozygous mutation in the SOS1 gene, resulting in an arg552-to-ser (R522S) substitution. She presented at 13 years with swelling and severe pain in her right foot and ankle. History and physical examination showed that she had multiple features of Noonan syndrome. Mascheroni et al. (2008) suggested that PVNS is a proliferative lesion that is part of the phenotypic spectrum of Noonan syndrome. Another mutation in this same codon (R552G; 182530.0004) has also been reported.
In 2 brothers, born of consanguineous parents, with Noonan syndrome-4 (NS4; 610733) and multiple giant cell lesions, Hanna et al. (2009) identified a heterozygous 1294T-C transition in exon 10 of the SOS1 gene, resulting in a trp432-to-arg (W432R) substitution within the pleckstrin homology domain. One boy presented at age 4.5 years with a 2-year history of bilateral progressive swelling of the mandible. Radiographic studies showed multilocular lesions of the mandibular rami, consistent with giant cell lesions. The boy's 6.5-year-old brother presented with severe pulmonary valvular stenosis and was found to have similar multilocular lesions of the mandible as his brother. Both boys had characteristic facial features of Noonan syndrome, including high anterior hairline with frontal bossing, follicular hyperkeratosis of the forehead (keratosis pilaris), depressed nasal bridge, hypertelorism, downslanting palpebral fissures, and low-set and posteriorly angulated ears with thick helices. Other features included short neck and widely spaced nipples. Both showed normal development and normal stature. The father showed milder features of the disorder, with long face, downslanting palpebral fissures, low-set ears, and widely spaced nipples, and was also heterozygous for the W432R mutation.
In 10 affected members of a 3-generation family segregating Noonan syndrome-4 (NS4; 610733), van Trier et al. (2017) identified a heterozygous c.3134C-G transversion (c.3134C-G, NM_005633.3) in the SOS1 gene, resulting in a pro1045-to-arg (P1045R) substitution at a moderately conserved residue. The mutation was identified in the proband (patient IV-8) by next-generation sequencing of an NS gene panel and in additional family members by Sanger sequencing. No other pathogenic mutations or variants of uncertain significance were identified, and the mutation segregated with the disorder in the family. There was a range of clinical expression among the 10 family members from almost no NS4 characteristics to a typical presentation. The family was part of an NS cohort previously studied by van Trier et al. (2015).
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