Department of Medical Genetics, Tohoku University School of Medicine, Sendai.
Immunology and Inflammatory Disease Field, Asubio Pharma Co., Ltd, Kobe.
Hum Mol Genet. 2019 Jan 1;28(1):74-83. doi: 10.1093/hmg/ddy333.
Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.
心面脂-骨综合征（CFC）是一种由 BRAF、KRAS、MAP2K1 和 MAP2K2 种系突变引起的遗传疾病，其特征为生长迟缓、心脏缺陷、面型畸形和皮肤异常。我们之前曾报道过，表达 CFC 综合征相关突变 Braf Q241R 的嵌合小鼠因胃肠道功能障碍而出现生长迟缓。然而，其他与生长迟缓相关的因素，包括软骨生成和内分泌特征，尚未被检测到。在这里，我们发现 3 周和 4 周龄的 BrafQ241R/+ 小鼠体重和体长降低，并且其近端胫骨生长板宽度减小。此外，与 Braf+/+ 小鼠相比，BrafQ241R/+ 小鼠的生长板增殖和肥大软骨细胞区缩小。免疫组织化学分析显示，BrafQ241R/+ 小鼠肥大软骨细胞中的细胞外信号调节激酶（ERK）激活增强。与生长迟缓以及生长板宽度减小相一致，3 周和 4 周龄的 BrafQ241R/+ 小鼠血清胰岛素样生长因子 1（IGF-1）和 IGF 结合蛋白 3（IGFBP-3）水平降低。C 型利钠肽（CNP）是一种促进软骨内骨生长的物质，也是 FGFR3-RAF1-MEK/ERK 信号通路的有效抑制剂，对 Braf+/+ 和 BrafQ241R/+ 小鼠进行 CNP 处理可增加其体长和尾长。综上所述，软骨细胞中的 ERK 激活和血清 IGF-1/IGFBP-3 水平降低可能与 BrafQ241R/+ 小鼠的生长迟缓有关。我们的数据还表明，CNP 可能是 CFC 综合征的潜在治疗靶点。
