RGD Reference Report - Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. - Rat Genome Database

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Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Authors: Tartaglia, M  Pennacchio, LA  Zhao, C  Yadav, KK  Fodale, V  Sarkozy, A  Pandit, B  Oishi, K  Martinelli, S  Schackwitz, W  Ustaszewska, A  Martin, J  Bristow, J  Carta, C  Lepri, F  Neri, C  Vasta, I  Gibson, K  Curry, CJ  Siguero, JP  Digilio, MC  Zampino, G  Dallapiccola, B  Bar-Sagi, D  Gelb, BD 
Citation: Tartaglia M, etal., Nat Genet. 2007 Jan;39(1):75-9. Epub 2006 Dec 13.
RGD ID: 11063026
Pubmed: PMID:17143282   (View Abstract at PubMed)
DOI: DOI:10.1038/ng1939   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Noonan syndrome 4  IAGP 11063026DNA:missense mutations:exon:multipleRGD 
Noonan syndrome 4  ISOSOS1 (Homo sapiens)11063026; 11063026DNA:missense mutations:exon:multipleRGD 

Objects Annotated

Genes (Rattus norvegicus)
Sos1  (SOS Ras/Rac guanine nucleotide exchange factor 1)

Genes (Mus musculus)
Sos1  (SOS Ras/Rac guanine nucleotide exchange factor 1)

Genes (Homo sapiens)
SOS1  (SOS Ras/Rac guanine nucleotide exchange factor 1)


Additional Information