title: Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.
abstract: Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. mtartaglia@iss.it
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Kamlesh K
authors.initials: KK
authors.lastname: Yadav
authors.forename: Valentina
authors.initials: V
authors.lastname: Fodale
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Pandit
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Oishi
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.forename: Wendy
authors.initials: W
authors.lastname: Schackwitz
authors.forename: Anna
authors.initials: A
authors.lastname: Ustaszewska
authors.forename: Joel
authors.initials: J
authors.lastname: Martin
authors.forename: James
authors.initials: J
authors.lastname: Bristow
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Cinzia
authors.initials: C
authors.lastname: Neri
authors.forename: Isabella
authors.initials: I
authors.lastname: Vasta
authors.forename: Kate
authors.initials: K
authors.lastname: Gibson
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.forename: Juan Pedro López
authors.initials: JP
authors.lastname: Siguero
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis / Q000379:methods; D005820:Genetic Testing; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics*; D020837:SOS1 Protein / Q000737:chemistry / Q000235:genetics*; D014162:Transfection
chemical_list: D020837:SOS1 Protein