title: Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype.
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.
authors.affiliation: Department of Medical Genetics and.
authors.forename: Mitsuji
authors.initials: M
authors.lastname: Moriya
authors.affiliation: Department of Medical Genetics and.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Department of Pediatric Cardiology and Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyagawa-Tomita
authors.affiliation: Department of Pediatrics, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Nakashima
authors.affiliation: Department of Medical Genetics and.
authors.forename: Daiju
authors.initials: D
authors.lastname: Oba
authors.affiliation: Department of Medical Genetics and.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan and.
authors.forename: Misato
authors.initials: M
authors.lastname: Hashi
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Medical Genetics and National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Medical Genetics and aokiy@med.tohoku.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004452:Echocardiography; D004476:Ectodermal Dysplasia / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics; D005260:Female; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf