RGD Reference Report - Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome. - Rat Genome Database

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Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome.

Authors: Urosevic, J  Sauzeau, V  Soto-Montenegro, ML  Reig, S  Desco, M  Wright, EM  Canamero, M  Mulero, F  Ortega, S  Bustelo, XR  Barbacid, M 
Citation: Urosevic J, etal., Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5015-20. doi: 10.1073/pnas.1016933108. Epub 2011 Mar 7.
RGD ID: 11567236
Pubmed: PMID:21383153   (View Abstract at PubMed)
PMCID: PMC3064394   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1016933108   (Journal Full-text)

RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardio-facio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-RAF, MEK1, MEK2, and K-RAS. B-RAF is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-RafLSLV600E allele. This targeted allele allows low levels of expression of B-RafV600E, a constitutively active B-Raf kinase first identified in human melanoma. B-Raf+/LSLV600E mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf+/LSLV600E mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cardiofaciocutaneous syndrome  ISOBraf (Mus musculus)11567236; 11567236 RGD 
cardiofaciocutaneous syndrome  IMP 11567236 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Braf  (B-Raf proto-oncogene, serine/threonine kinase)

Genes (Mus musculus)
Braf  (Braf transforming gene)

Genes (Homo sapiens)
BRAF  (B-Raf proto-oncogene, serine/threonine kinase)


Additional Information