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. 2013 Apr;4(4):179-83.
doi: 10.1159/000348327. Epub 2013 Mar 26.

Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations

J Soblet  1 , N Limaye, M Uebelhoer, L M Boon, M Vikkula
Affiliations

Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations

J Soblet et al. Mol Syndromol. 2013 Apr.

Abstract

Venous malformations (VMs) are the most frequent vascular malformations referred to specialized vascular anomaly centers. A rare (1-2%) familial form, termed cutaneomucosal venous malformation (VMCM), is caused by gain-of-function mutations in TIE2. More recently, sporadic VMs, characterized by the presence of large unifocal lesions, were shown to be caused by somatic mutations in TIE2. These include a frequent L914F change, and a series of double mutations in cis. All of which cause ligand-independent receptor hyperphosphorylation in vitro. Here, we expanded our study to assess the range of mutations that cause sporadic VM. To test for somatic changes, we screened the entire coding region of TIE2 in cDNA from resected VMs by direct sequencing. We detected TIE2 mutations in 17/30 (56.7%) of the samples. In addition to previously detected mutations, we identified 7 novel somatic intracellular TIE2 mutations in sporadic VMs, including 3 that cause premature protein truncation.

Keywords: Hyperphosphorylation; Receptor tyrosine kinase; Somatic mutation; Sporadic; TIE2/TEK; Vascular malformation; Venous malformation.

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Figures

Fig. 1
Fig. 1
Sporadic VM on A the neck, B genitals, C chest, and D thigh.
Fig. 2
Fig. 2
A Somatic changes identified in patients with sporadic VM. Mutations identified in original (DNA) tissue screen on the left; additional mutations identified in this (cDNA) tissue screen on the right. B Five individuals had TIE2 double substitutions. T1105N + T1106P occurred in 2 patients. C Ligand-independent phosphorylation of the double mutants T1105N + T1106P and T1105N + G1115* compared with constituent single mutants, WT, common germline mutant R849W and common somatic mutant L914F. NT = Non-transfected controls.
Fig. 3
Fig. 3
TIE2 intracellular protein structure showing the nucleotide binding loop (red), the catalytic loop (green), the activation loop (blue), the kinase insert domain (pink), the C-terminal tail (yellow), and positions of somatic mutations (orange). This figure was prepared using Cn3D (http://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml).
See this image and copyright information in PMC

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