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.

• Authors: Amy E Roberts, Toshiyuki Araki, Kenneth D Swanson, Kate T Montgomery, Taryn A Schiripo, Victoria A Joshi, Li Li, Yosuf Yassin, Alex M Tamburino, Benjamin G Neel, Raju S Kucherlapati
• Journal: Nature genetics (Nat Genet) Vol. 39 Issue 1 Pg. 70-4 (Jan 2007) ISSN: 1061-4036 [Print] United States
• PMID: 17143285 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• SOS1 Protein
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• DNA Mutational Analysis
• Female
• Genetic Testing
• Germ-Line Mutation
• Humans
• Infant
• Intracellular Signaling Peptides and Proteins (genetics)
• Male
• Models, Biological
• Models, Molecular
• Noonan Syndrome (genetics)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases (genetics)
• SOS1 Protein (chemistry, genetics)