Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype
Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype
复制标题
DOI：
10.1093/hmg/ddv435
复制
发表时间：
2015-12-20
影响因子：
3.5
通讯作者：
Aoki, Yoko
中科院分区：
文献类型：
--
作者：
Moriya, Mitsuji;Inoue, Shin-ichi;Aoki, Yoko
RAS通路的激活与称为RAS病的肿瘤发生和发育障碍有关。在50-75%的心-面-皮肤（CFC）综合征患者中发现了BRAF的种系突变，CFC综合征的特征是先天性心脏缺陷、独特的面部特征、身材矮小和外胚层异常。我们最近证明，在C57 BL/6 J背景下表达Braf Q241 R突变（对应于CFC综合征中最常见的BRAF突变（Q257 R））的小鼠是胚胎/新生儿致死性的，具有多种先天性缺陷，使我们无法分析出生后的表型后果。在这里，为了进一步探讨CFC综合征的发病机制，我们将这些小鼠回交到BALB/c或ICR/CD-1遗传背景上。在混合（BALB/c和C57 BL/6 J）背景下，所有杂合子Braf（Q241 R/+）小鼠在出生至24周期间死亡，并表现出生长迟缓、稀疏和皱褶的皮毛、肝坏死和房间隔缺损（ASD）。相比之下，31%的杂合Braf（Q241 R/+）ICR小鼠存活超过74周。存活的Braf（Q241 R/+）ICR小鼠表现出生长迟缓、稀疏和皱褶的皮毛、驼背外观、颅面畸形、长指甲和/或营养不良的指甲、多余的手指和卵巢囊肿。Braf（Q241 R/+）ICR小鼠在情境恐惧条件反射测试中也表现出学习缺陷。超声心动图显示Braf（Q241 R/+）ICR小鼠存在肺动脉狭窄和ASD，并通过组织学分析证实。这些数据表明，杂合子Braf（Q241 R/+）ICR小鼠出生后表现出与CFC综合征相似的表型，这将有助于阐明RASopathies的发病机制和潜在的治疗策略。
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.