Germline gain-of-function mutations in SOS1 cause Noonan syndrome

Nat Genet. 2007 Jan;39(1):70-4. doi: 10.1038/ng1926. Epub 2006 Dec 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • SOS1 Protein / genetics*

Substances

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

Associated data

  • RefSeq/NM_002834
  • RefSeq/NM_004333
  • RefSeq/NM_004383
  • RefSeq/NM_005633
  • RefSeq/NM_006939
  • RefSeq/NM_012219
  • RefSeq/NM_018440
  • RefSeq/NM_080549