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.
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SOS1, under selection in domesticated foxes, affects MAPK signaling, bringing about Noonan phenotypes.
“Upstream of BRAF, SOS1, under selection in domesticated foxes, affects MAPK signaling, bringing about Noonan phenotypes [74].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [74]
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- Authors
- Roberts, A. E., Araki, T., Swanson, K. D., Montgomery, K. T., Schiripo, T. A., Joshi, V. A., Li, L., Yassin, Y., Tamburino, A. M., Neel, B. G., & Kucherlapati, R. S.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Neel, Benjamin G
- Venue
- Nature Genetics
- Published
- 2006-12-03
- Volume
- 39
- Issue
- 1
- Pages
- 70-74
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2068804834
- Cited by
- 605
- References
- 44
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 29 · 2023: 14 · 2022: 27 · 2021: 29 · 2020: 20 · 2019: 28 · 2018: 13 · 2017: 24 · 2016: 20 · 2015: 21 · 2014: 30 · 2013: 32 · 2012: 37
- FWCI
- 20.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R37CA49152, R37CA049152)
- National Institute of Dental and Craniofacial Research (R01DE016140, DE-16140)
- National Center for Research Resources (M01-RR02172, M01RR002172)
- NIH Clinical Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Noonan syndrome, SOS1, gain-of-function mutations, Ras guanine nucleotide exchange factor, SHP2, PTPN11, congenital heart disease, missense mutations, Ras activation, leukemia predisposition
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, DNA Mutational Analysis, Female, Genetic Testing, Humans, Infant, Male, Models, Biological, Models, Molecular, Noonan Syndrome, Protein Tyrosine Phosphatases, Germ-Line Mutation, SOS1 Protein, Intracellular Signaling Peptides and Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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