title: 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.affiliation: Harvard Partners Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Swanson
authors.forename: Kate T
authors.initials: KT
authors.lastname: Montgomery
authors.forename: Taryn A
authors.initials: TA
authors.lastname: Schiripo
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Joshi
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yosuf
authors.initials: Y
authors.lastname: Yassin
authors.forename: Alex M
authors.initials: AM
authors.lastname: Tamburino
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Raju S
authors.initials: RS
authors.lastname: Kucherlapati
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D009634:Noonan Syndrome / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D020837:SOS1 Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020837:SOS1 Protein; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases