Background:Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis.Methods:Exome sequencing was performed on 412 probands and family members from our DCM cohort, identifying several SOS1 variants with potential disease involvement. As several lines of evidence have implicated dysregulated rat sarcoma signaling in the pathogenesis of DCM, we assessed functional impact of each variant on the activation of ERK (extracellular signal-regulated kinase), AKT (protein kinase B), and JNK (c-Jun N-terminal kinase) pathways. Relative expression levels were determined by Western blot in HEK293T cells transfected with variant or wild-type human SOS1 expression constructs.Results:A rare SOS1 variant [c.571G>A, p.(Glu191Lys)] was found to segregate alongside an A-band TTN truncating variant in a pedigree with aggressive, early-onset DCM. Reduced disease severity in the absence of the SOS1 variant suggested its potential involvement as a genetic risk factor for DCM in this family. Exome sequencing identified 5 additional SOS1 variants with potential disease involvement in 4 other families [c.1820T>C, p.(Ile607Thr); c.2156G>C, p.(Gly719Ala); c.2230A>G, p.(Arg744Gly); c.2728G>C, p.(Asp910His); c.3601C>T, p.(Arg1201Trp)]. Impacted amino acids occupied a number of functional domains relevant to SOS1 activity, including the N-terminal histone fold, as well as the C-terminal REM (rat sarcoma exchange motif), CDC25 (cell division cycle 25), and PR (proline-rich) tail domains. Increased phosphorylated ERK expression relative to wild-type levels was seen for all 6 SOS1 variants, paralleling known disease-relevant SOS1 signaling profiles.Conclusions:These data support gain-of-function variation in SOS1 as a contributing factor to isolated DCM.

中文翻译：

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扩张型心肌病中的 SOS1 功能获得性变异。

背景：扩张型心肌病 (DCM) 是一种遗传异质性心脏病，其特征是进行性心室扩大和收缩功能降低。这里，我们报告基因和功能分析牵连大鼠肉瘤信号蛋白，SOS1（SON sevenless同源物1），在DCM pathogenesis.Methods：412名上先证者和家庭成员从我们的DCM组群进行基因组测序，识别几个SOS1具有潜在疾病参与的变异。由于几条证据表明 DCM 发病机制中的大鼠肉瘤信号传导失调，我们评估了每个变体对 ERK（细胞外信号调节激酶）、AKT（蛋白激酶 B）和 JNK（c-Jun N-末端激酶）途径。在用变异或野生型人SOS1表达构建体转染的 HEK293T 细胞中，通过蛋白质印迹确定相对表达水平。 结果：发现一种罕见的SOS1变异 [c.571G>A, p.(Glu191Lys)] 与 A-带TTN截断变异的谱系具有侵略性，早发性 DCM。在没有SOS1的情况下疾病严重程度降低变体表明其潜在参与该家族中 DCM 的遗传风险因素。外显子组测序确定了 5 个额外的SOS1变异，这些变异与其他 4 个家族的潜在疾病有关 [c.1820T>C, p.(Ile607Thr); c.2156G>C，p.(Gly719Ala)；c.2230A>G，p.(Arg744Gly)；c.2728G>C，p.(Asp910His)；c.3601C>T，p.(Arg1201Trp)]。受影响的氨基酸占据了许多与 SOS1 活性相关的功能域，包括 N 端组蛋白折叠，以及 C 端 REM（大鼠肉瘤交换基序）、CDC25（细胞分裂周期 25）和 PR（脯氨酸-丰富的）尾域。所有 6 个SOS1变体均观察到相对于野生型水平的磷酸化 ERK 表达增加，与已知的疾病相关SOS1平行信号配置文件。结论：这些数据支持SOS1中的功能增益变化是孤立 DCM 的一个促成因素。