Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype

Hum Mol Genet. 2015 Dec 20;24(25):7349-60. doi: 10.1093/hmg/ddv435. Epub 2015 Oct 15.


Activation of the RAS pathway has been implicated in oncogenesis and developmental disorders called RASopathies. Germline mutations in BRAF have been identified in 50-75% of patients with cardio-facio-cutaneous (CFC) syndrome, which is characterized by congenital heart defects, distinctive facial features, short stature and ectodermal abnormalities. We recently demonstrated that mice expressing a Braf Q241R mutation, which corresponds to the most frequent BRAF mutation (Q257R) in CFC syndrome, on a C57BL/6J background are embryonic/neonatal lethal, with multiple congenital defects, preventing us from analyzing the phenotypic consequences after birth. Here, to further explore the pathogenesis of CFC syndrome, we backcrossed these mice onto a BALB/c or ICR/CD-1 genetic background. On a mixed (BALB/c and C57BL/6J) background, all heterozygous Braf(Q241R/+) mice died between birth and 24 weeks and exhibited growth retardation, sparse and ruffled fur, liver necrosis and atrial septal defects (ASDs). In contrast, 31% of the heterozygous Braf(Q241R/+) ICR mice survived over 74 weeks. The surviving Braf(Q241R/+) ICR mice exhibited growth retardation, sparse and ruffled fur, a hunched appearance, craniofacial dysmorphism, long and/or dystrophic nails, extra digits and ovarian cysts. The Braf(Q241R/+) ICR mice also showed learning deficits in the contextual fear-conditioning test. Echocardiography indicated the presence of pulmonary stenosis and ASDs in the Braf(Q241R/+) ICR mice, which were confirmed by histological analysis. These data suggest that the heterozygous Braf(Q241R/+) ICR mice show similar phenotypes as CFC syndrome after birth and will be useful for elucidating the pathogenesis and potential therapeutic strategies for RASopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Echocardiography
  • Ectodermal Dysplasia / genetics
  • Facies
  • Failure to Thrive / genetics
  • Female
  • Genotype
  • Heart Defects, Congenital / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Electron
  • Mutation / genetics
  • Proto-Oncogene Proteins B-raf / genetics*


  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf

Supplementary concepts

  • Cardiofaciocutaneous syndrome