Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.
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.
Tartaglia
Marco
M
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. mtartaglia@iss.it
Pennacchio
Len A
LA
Zhao
Chen
C
Yadav
Kamlesh K
KK
Fodale
Valentina
V
Sarkozy
Anna
A
Pandit
Bhaswati
B
Oishi
Kimihiko
K
Martinelli
Simone
S
Schackwitz
Wendy
W
Ustaszewska
Anna
A
Martin
Joel
J
Bristow
James
J
Carta
Claudio
C
Lepri
Francesca
F
Neri
Cinzia
C
Vasta
Isabella
I
Gibson
Kate
K
Curry
Cynthia J
CJ
Siguero
Juan Pedro López
JP
Digilio
Maria Cristina
MC
Zampino
Giuseppe
G
Dallapiccola
Bruno
B
Bar-Sagi
Dafna
D
Gelb
Bruce D
BD
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
D020837:SOS1 Protein