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

Mitsuji Moriya, Shin Ichi Inoue, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Daiju Oba, Tetsuya Niihori, Misato Hashi, Hiroshi Ohnishi, Shigeo Kure, Yoichi Matsubara, Yoko Aoki

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 BrafQ241R/+ 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 BrafQ241R/+ ICR mice survived over 74 weeks. The surviving BrafQ241R/+ 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 BrafQ241R/+ ICR mice also showed learning deficits in the contextual fear-conditioning test. Echocardiography indicated the presence of pulmonary stenosis and ASDs in the BrafQ241R/+ ICR mice, which were confirmed by histological analysis. These data suggest that the heterozygous BrafQ241R/+ ICR mice show similar phenotypes as CFC syndrome after birth and will be useful for elucidating the pathogenesis and potential therapeutic strategies for RASopathies.

Original languageEnglish
Pages (from-to)7349-7360
Number of pages12
JournalHuman molecular genetics
Volume24
Issue number25
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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