Department of Pediatrics, University of California Davis, Sacramento, CA 95817, USA.
UC Davis MIND Institute, Sacramento, CA 95817, USA.
Dis Model Mech. 2022 Feb 1;15(2). doi: 10.1242/dmm.049166. Epub 2021 Nov 19.
Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes caused by mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due, in part, to inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction in myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction in p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.
Costello 综合征（CS）是一种先天性疾病，由经典 Ras/丝裂原活化蛋白激酶（Ras/MAPK）通路中的异质激活种系 HRAS 突变引起。CS 是 RAS 相关疾病之一，这是一大类由 Ras/MAPK 通路中各种成分的突变引起的综合征。严重影响生活质量的表型的一个重要部分是张力减退。为了更好地理解 CS 中张力减退的机制，利用具有激活 HrasG12V 等位基因的小鼠模型进行了研究。我们发现了一种骨骼肌肉疾病，部分原因是胚胎肌发生和肌纤维形成受到抑制，导致肌纤维大小和数量减少，从而导致肌肉质量和力量下降。除了 Ras/MAPK 和 PI3K/AKT 通路的过度激活外，p38 信号也显著减少，以及与肌病表型一致的全局转录改变。使用 MEK 抑制剂抑制 Ras/MAPK 通路信号转导，在体外和体内均能挽救 HrasG12V 肌病表型，表明增加的 MAPK 信号转导是 CS 中肌肉表型的主要原因。
