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

authors

  • UROSEVIC, JELENA
  • SAUZEAU, VINCENT
  • SOTO MONTENEGRO, MARIA L.
  • REIG, SANTIAGO
  • DESCO MENENDEZ, MANUEL
  • WRIGHT, EMMA M. BURKITT
  • CAÑAMERO, MARTA
  • MULERO, FRANCISCA
  • ORTEGA, SAGRARIO
  • BUSTELO, XOXE R.
  • BARBACID, MARIANO

publication date

  • March 2011

start page

  • 5015

end page

  • 5020

issue

  • 12

volume

  • 108

international standard serial number (ISSN)

  • 1091-6490

electronic international standard serial number (EISSN)

  • 0027-8424

abstract

  • 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.

keywords

  • b-raf signaling; developmental defects; chromaffin-derived tumor