SOS1 – Noonan Syndrome

Noonan syndrome (MONDO:0018997) is an autosomal dominant RASopathy characterized by short stature, congenital heart defects, and distinctive facial features. Mutations in genes of the RAS/MAPK pathway underlie NS, with PTPN11 accounting for ~50% of cases and SOS1 (HGNC:11187) identified as the second most frequent gene, implicated in 20–25% of mutation‐positive cohorts (PMID:17586837).

In an early European series of 40 patients, a novel SOS1 c.796A>G (p.Thr266Lys) substitution was found in one individual lacking PTPN11 mutations, confirming SOS1’s minor but significant role in NS (PMID:18678287). Subsequent high‐throughput screening uncovered 33 distinct SOS1 variants across over 200 unrelated probands, predominantly missense and in‐frame indels clustering in domains critical for autoinhibition (PMID:21387466).

Segregation analysis in a three‐generation pedigree demonstrated co‐segregation of the heterozygous c.3134C>G (p.Pro1045Arg) variant with NS features in ten affected relatives (PMID:28884940).

The SOS1 variant spectrum is almost exclusively gain‐of‐function missense changes. Recurrent alleles at residue Arg552 (e.g., c.1655G>A (p.Arg552Lys)) appear in multiple populations, while de novo changes such as c.1294T>C (p.Trp432Arg) have been reported in NS with multiple giant cell lesions (PMID:19438935).

Functional assays confirm that NS‐associated variants disrupt SOS1 autoinhibition and enhance RAS/MAPK signaling. N‐terminal deletions impair EGF‐driven Ras activation (PMID:9447973), while the T158A mutation prolongs ERK1/2 activation and modulates PI3K/AKT signaling (PMID:23528009). NMR‐based profiling of SOS1 mutants further demonstrated accelerated nucleotide exchange and membrane recruitment consistent with gain‐of‐function (PMID:23487764). Initial in vivo studies revealed that Sos1-null mice exhibit cardiovascular and developmental defects, supporting a pivotal role in growth factor signaling (PMID:9030684).

No studies have refuted SOS1’s role in NS, though incomplete penetrance has been noted for variants such as c.755T>C (p.Ile252Thr) detected in asymptomatic carriers (PMID:25712082).

Collectively, the presence of >200 unrelated probands with SOS1 gain‐of‐function variants, multi‐family segregation, and concordant functional data over >15 years establishes a definitive gene–disease relationship. Key Take-home: Gain-of-function SOS1 mutations cause an autosomal dominant form of Noonan syndrome, providing immediate diagnostic and counseling utility.

References

• Journal of medical genetics • 2007 • SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. PMID:17586837
• European journal of medical genetics • 2008 • Clinical and molecular characterization of 40 patients with Noonan syndrome. PMID:18678287
• Human mutation • 2011 • SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. PMID:21387466
• American journal of medical genetics. Part A • 2017 • Variable phenotypic expression in a large Noonan syndrome family segregating a novel SOS1 mutation. PMID:28884940
• Journal of cutaneous medicine and surgery • 2009 • SOS1: a new player in the Noonan-like/multiple giant cell lesion syndrome. PMID:19438935
• Journal of receptor and signal transduction research • 2013 • A novel SOS1 mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways. PMID:23528009
• Genes & development • 1997 • Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for Sos1 in EGFR signaling and development. PMID:9030684
• Molecular and cellular biology • 1998 • N terminus of Sos1 Ras exchange factor: critical roles for the Dbl and pleckstrin homology domains. PMID:9447973
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • NMR-based functional profiling of RASopathies and oncogenic RAS mutations. PMID:23487764
• European journal of human genetics : EJHG • 2015 • Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family. PMID:25712082

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