Document Detail

Germline gain-of-function mutations in SOS1 cause Noonan syndrome.
MedLine Citation:
PMID:  17143285     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-12-03
Journal Detail:
Title:  Nature genetics     Volume:  39     ISSN:  1061-4036     ISO Abbreviation:  Nat. Genet.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-28     Completed Date:  2007-02-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  70-4     Citation Subset:  IM    
Harvard Partners Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts 02115, USA.
Data Bank Information
Bank Name/Acc. No.:
RefSeq/NM_002834;  NM_004333;  NM_004383;  NM_005633;  NM_006939;  NM_012219;  NM_018440;  NM_080549
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MeSH Terms
Child, Preschool
DNA Mutational Analysis
Genetic Testing
Germ-Line Mutation*
Intracellular Signaling Peptides and Proteins / genetics
Models, Biological
Models, Molecular
Noonan Syndrome / genetics*
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatases / genetics
SOS1 Protein / chemistry,  genetics*
Grant Support
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/SOS1 Protein; EC protein, human; EC Tyrosine Phosphatase, Non-Receptor Type 11; EC Tyrosine Phosphatases
Comment In:
Nat Genet. 2007 Jan;39(1):8-9   [PMID:  17192780 ]

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