Division of Medical Genetics, A. I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Department of Biomedical Research, A. I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Eur J Hum Genet. 2020 Nov;28(11):1548-1554. doi: 10.1038/s41431-020-0662-4. Epub 2020 Jun 4.
Specific activating missense HRAS variants cause Costello syndrome (CS), a RASopathy with recognizable facial features. The majority of these dominant disease causing variants affect the glycine residues in position 12 or 13. A clinically suspected CS diagnosis can be confirmed through identification of a dominant pathogenic HRAS variant. A novel HRAS variant predicting p.(Glu62_Arg68dup) was identified in an individual with hypertrophic cardiomyopathy, Chiari 1 malformation and ectodermal findings consistent with a RASopathy. Functional studies showed that the p.Glu62_Arg68dup alteration affects HRAS interaction with effector protein PIK3CA (catalytic subunit of phosphoinositide 3-kinase) and the regulator neurofibromin 1 (NF1) GTPase-activating protein (GAP). HRAS binding with effectors rapidly accelerated fibrosarcoma (RAF1), RAL guanine nucleotide dissociation stimulator (RALGDS) and phospholipase C1 (PLCE1) was enhanced. Accordingly, p.Glu62_Arg68dup increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF1, whereas AKT phosphorylation downstream of PI3K was not significantly affected. Growth factor stimulation revealed that expression of HRAS abolished the HRAS' capacity to modulate downstream signaling. Our data underscore that different qualities of dysregulated HRAS-dependent signaling dynamics determine the clinical severity in CS.
特定的激活性错义 HRAS 变体导致 Costello 综合征（CS），这是一种具有可识别面部特征的 RAS 病。这些显性致病变体大多数影响位置 12 或 13 的甘氨酸残基。通过鉴定显性致病 HRAS 变体可以确认临床疑似 CS 诊断。在一名患有肥厚型心肌病、Chiari 1 畸形和外胚层表现的个体中发现了一种新的 HRAS 变体，预测为 p.(Glu62_Arg68dup)，该变体与 RAS 病一致。功能研究表明，p.Glu62_Arg68dup 改变影响 HRAS 与效应蛋白 PIK3CA（磷酸肌醇 3-激酶的催化亚基）和调节蛋白神经纤维瘤 1（NF1）GTPase 激活蛋白（GAP）的相互作用。HRAS 与效应物的结合迅速加速了纤维肉瘤（RAF1）、RAL 鸟嘌呤核苷酸解离刺激因子（RALGDS）和磷脂酶 C1（PLCE1）的形成。因此，p.Glu62_Arg68dup 增加了 RAF1 下游 MEK1/2 和 ERK1/2 的稳态磷酸化，而 PI3K 下游的 AKT 磷酸化没有受到显著影响。生长因子刺激表明，HRAS 的表达消除了 HRAS 调节下游信号的能力。我们的数据强调，不同质量的失调 HRAS 依赖性信号动力学决定了 CS 的临床严重程度。
