Open AccessConstitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome
Author(s) -
Jelena Urosevic,
Vincent Sauzeau,
María Luisa Soto-Montenegro,
Santiago Reig,
Manuel Desco,
Emma Mm Burkitt Wright,
Marta Cañamero,
Francisca Mulero,
Sagrario Ortega,
Xosé R. Bustelo,
Mariano Barbacid
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1016933108
Subject(s) - biology , allele , cancer research , germline , kinase , neuroblastoma , locus (genetics) , gene , genetics , cell culture
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-Raf LSLV600E 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.