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^{Glu62_Arg68dup} 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^{Glu62_Arg68dup} 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.

特定的激活错义HRAS变异会导致 Costello 综合征 (CS)，这是一种具有可识别面部特征的 RAS 病。这些显性致病变异中的大多数影响位置 12 或 13 的甘氨酸残基。临床上怀疑的 CS 诊断可以通过鉴定显性致病性HRAS变异来确认。一种新颖的HRAS变异预测 p.(Glu62_Arg68dup) 在肥厚型心肌病、Chiari 1 畸形和与 RAS 病一致的外胚层发现的个体中被鉴定。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）和调节神经纤维蛋白 1 (NF1) GTP 酶激活蛋白 (GAP) 的相互作用。HRAS ^{Glu62_Arg68dup}与效应子的结合迅速加速纤维肉瘤 (RAF1)、RAL 鸟嘌呤核苷酸解离刺激剂 (RALGDS) 和磷脂酶 C1 (PLCE1) 得到增强。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 磷酸化没有受到显着影响。生长因子刺激表明 HRAS ^{Glu62_Arg68dup 的}表达消除了 HRAS 调节下游信号的能力。我们的数据强调，失调的 HRAS 依赖性信号动力学的不同性质决定了 CS 的临床严重程度。