The functional role of BRAF in cardiac development and bone formation

• Project/Area Number: 15K19598
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Inoue Shin-ichi 東北大学, 医学系研究科, 助教 (70622091)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: CFC症候群 / RASopathies / RAS/MAPKシグナル伝達経路 / BRAF / 先天性心疾患 / 疾患モデルマウス / 遺伝性疾患 / マウスモデル / 肥大型心筋症 / 骨格形成異常 / 成長障害

Outline of Final Research Achievements

Germline mutations in BRAF have been identified in 70% of patients with cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, distinctive facial features, short stature and ectodermal abnormalities. We recently demonstrated that mice expressing a Braf Q241R mutation 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 an ICR genetic background. The BrafQ241R/+ ICR mice exhibited growth retardation, sparse and ruffled fur, a hunched appearance, craniofacial dysmorphism and heart defects, including pulmonary stenosis and atrial septal defects. 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 CFC syndrome.

Research Products

• [Journal Article] Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype (2015)
  • Author(s): Moriya M, Inoue S, Miyagawa-Tomita S, Nakashima Y, Oba D, Niihori T, Hashi M, Ohnishi H, Kure S, Matsubara Y, Aoki Y.
  • Journal Title: Human molecular genetics Volume: 24 Pages: 7349-60
  • DOI: 10.1093/hmg/ddv435
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype (2016)
  • Author(s): Shin-ichi Inoue
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都国際会館（京都）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] がん原遺伝子BRAFの機能獲得性変異は先天性異常を引き起こす (2015)
  • Author(s): 井上晋一
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（神戸）
  • Year and Date: 2015-12-01