| 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 | Marco Tartaglia, Len A Pennacchio, Chen Zhao, Kamlesh K Yadav, Valentina Fodale, Anna Sarkozy, Bhaswati Pandit, Kimihiko Oishi, Simone Martinelli, Wendy Schackwitz, Anna Ustaszewska, Joel Martin, James Bristow, Claudio Carta, Francesca Lepri, Cinzia Neri, Isabella Vasta, Kate Gibson, Cynthia J Curry, Juan Pedro López Siguero, Maria Cristina Digilio, Giuseppe Zampino, Bruno Dallapiccola, Dafna Bar-Sagi, Bruce D Gelb
(Affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. mtartaglia at iss.it)
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| Journal | Nature genetics
(Nat Genet)
Vol. 39
Issue 1
Pg. 75-9
(Jan 2007)
ISSN: 1061-4036 United States |
| PMID | 17143282
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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| Chemical References |
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| Topics |
- Animals
- COS Cells
- Cercopithecus aethiops
- DNA Mutational Analysis
(methods)
- Genetic Screening
- Humans
- Models, Molecular
- Mutation
- Noonan Syndrome
(genetics)
- SOS1 Protein
(chemistry, genetics)
- Transfection
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