Document Detail


Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.
MedLine Citation:
PMID:  17143282     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
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.     Date:  2006-12-13
Journal Detail:
Title:  Nature genetics     Volume:  39     ISSN:  1061-4036     ISO Abbreviation:  Nat. Genet.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-28     Completed Date:  2007-02-21     Revised Date:  2012-02-23    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  75-9     Citation Subset:  IM    
Affiliation:
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. mtartaglia@iss.it
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MeSH Terms
Descriptor/Qualifier:
Animals
COS Cells
Cercopithecus aethiops
DNA Mutational Analysis / methods
Genetic Testing
Humans
Models, Molecular
Mutation
Noonan Syndrome / genetics*
SOS1 Protein / chemistry,  genetics*
Transfection
Grant Support
ID/Acronym/Agency:
CA28146/CA/NCI NIH HHS; CA55360/CA/NCI NIH HHS; GGP04172//Telethon; HD01294/HD/NICHD NIH HHS; HL074728/HL/NHLBI NIH HHS; HL71207/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/SOS1 Protein
Comments/Corrections
Comment In:
Nat Genet. 2007 Jan;39(1):8-9   [PMID:  17192780 ]
Erratum In:
Nat Genet. 2007 Feb;39(2):276

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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