Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.
Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.
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DOI：
10.1038/ng.272
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发表时间：
2009-01
期刊：
影响因子：
30.8
通讯作者：
Vikkula, Miikka
中科院分区：
文献类型：
--
作者：
Limaye, Nisha;Wouters, Vinciane;Uebelhoer, Melanie;Tuominen, Marjut;Wirkkala, Riikka;Mulliken, John B.;Eklund, Lauri;Boon, Laurence M.;Vikkula, Miikka
内皮细胞酪氨酸激酶受体TIE2/TEK的种系替换导致一种罕见的遗传性静脉异常，即粘膜皮肤静脉畸形（VMCM）。我们现在在切除的VMCM中发现了导致受体功能丧失的体细胞二次撞击。我们评估了这种局部的、组织特异性的事件是否在更常见的散发性VM的病因学中起作用。在57名患者中的28名（49.1%）的病变中发现了8个体细胞TIE2突变，而在他们的血液或对照组织中未检测到。体细胞突变包括频繁的L914F改变，以及一系列顺式双突变，这些突变在体外都表现出与配体无关的超磷酸化。当L914F在HUVECs中过表达时，与野生型和常见的遗传R849W突变体不同，L914F表现出异常的定位和对配体的反应，表明它们可能具有不同的作用。在两例多灶性vm患者中存在相同的突变，提示远端内皮细胞异常有共同的起源。总之，这些数据表明散发性疾病可能是由导致罕见遗传形式的基因的体细胞变化来解释的，并且确定了TIE2通路作为VM的潜在治疗靶点。
Germline substitutions in the endothelial cell tyrosine kinase receptor TIE2/TEK cause a rare inherited form of venous anomalies, mucocutaneous venous malformations (VMCM). We now identified a somatic 2nd hit causing loss-of-function of the receptor in a resected VMCM. We assessed for whether such localized, tissue-specific events play a role in the etiology of the far more common sporadic VM. Eight somatic TIE2 mutations were identified in lesions from 28 out of 57 patients (49.1%), not detected in their blood or in control tissues. The somatic mutations included a frequent L914F change, and a series of double-mutations that occurred in cis, all of which show ligand-independent hyperphosphorylation in vitro. When overexpressed in HUVECs, L914F showed abnormal localization and response to ligand, differing from wild-type and the common inherited R849W mutant, suggesting they may have distinct effects. The presence of the same mutations in multifocal VMs in two patients, suggests a common origin for the abnormal endothelial cells in the distant sites. In conclusion, these data illustrate that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms, and pinpoint TIE2 pathways as potential therapeutic targets for VM.
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