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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 12; pp. 5015 - 5020
• Main Authors: Urosevic, Jelena, Sauzeau, Vincent, Soto-Montenegro, María L, Reig, Santiago, Desco, Manuel, Wright, Emma M. Burkitt, Cañamero, Marta, Mulero, Francisca, Ortega, Sagrario, Bustelo, Xosé R, Barbacid, Mariano
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.03.2011; National Acad Sciences
• Subjects: alleles; animal models; Animals; Bacteria; Biological Sciences; cataract; catecholamines; Chlorofluorocarbons; Congenital diseases; Costello syndrome; Disease Models, Animal; Ectodermal Dysplasia - enzymology; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - pathology; Ectodermal Dysplasia - therapy; Enzyme Activation - genetics; Facies; Failure to Thrive - enzymology; Failure to Thrive - genetics; Failure to Thrive - pathology; Failure to Thrive - therapy; Gene expression; Genetic mutation; Germ cells; Germ-Line Mutation; Grants; heart; Heart Defects, Congenital - enzymology; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Heart Defects, Congenital - therapy; Human genetics; Humans; Kinases; loci; longevity; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - genetics; MAP Kinase Kinase 2 - metabolism; Medical genetics; melanoma; Mice; Mice, Mutant Strains; Mutation; Myocardium; Neuroendocrine Tumors - enzymology; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Neuroendocrine Tumors - therapy; Pathology; pathophysiology; patients; Physiology; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Rodents; seizures; signal transduction; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1016933108

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.