Article ; Online: Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype.
2015 Volume 24, Issue 25, Page(s) 7349–7360
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | 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 |
| Chemical Substances | Braf protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2015-12-20 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1108742-0 |
| ISSN | 1460-2083 ; 0964-6906 |
| ISSN (online) | 1460-2083 |
| ISSN | 0964-6906 |
| DOI | 10.1093/hmg/ddv435 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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