Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype
| Autor: | Daiju Oba, Yoichi Matsubara, Yasumi Nakashima, Tetsuya Niihori, Yoko Aoki, Shin Ichi Inoue, Shigeo Kure, Mitsuji Moriya, Sachiko Miyagawa-Tomita, Misato Hashi, Hiroshi Ohnishi |
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| Rok vydání: | 2015 |
| Předmět: |
Heart Defects
Congenital Male Proto-Oncogene Proteins B-raf Ectodermal dysplasia Pathology medicine.medical_specialty Genotype Blotting Western Biology medicine.disease_cause Short stature Atrial septal defects Pathogenesis Mice Germline mutation Ectodermal Dysplasia Genetics medicine Animals Molecular Biology Genetics (clinical) Mutation Mice Inbred BALB C Facies General Medicine medicine.disease Phenotype Failure to Thrive Microscopy Electron Echocardiography Immunology Female medicine.symptom Carcinogenesis |
| Zdroj: | Human molecular genetics. 24(25) |
| ISSN: | 1460-2083 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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