Somatic TIE2 mutations in sporadic venous malformations
(2010) International Vascular Biology Meeting — Location: Los Angeles, USA (20.June.2010)
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- Abstract
- A rare (1-2%) familial form of venous anomalies, Cutaneomucosal Venous Malformation (VMCM), is caused by gain-of-function mutations in TIE2. 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. Double-mutations cause greater hyperphosphorylation than their constituent single mutations. Here, we expanded our study to assess the range of mutations that cause VMs, and evaluate for genotype-phenotype correlations. By sequencing the intracellular region of TIE2 in cDNA derived from resected VMs, we obtained information exclusively from normal/abnormal endothelial cells, the only TIE2-expressing cells in lesions. In addition to previously detected mutations, we identified five novel somatic intracellular TIE2 mutations in sporadic VMs, including two nonsense substitutions. These were absent in blood DNA. All are predicted to have deleterious effects on receptor function by bioinformatic analysis, and cause a ligand-independent hyperphosphorylation of the receptor. While L914F remains the most common change overall, the presence of double (cis) mutations seems to be enriched in individuals with rare, multifocal sporadic VMs. The presence of the same mutations in distant lesions in these individuals, suggests they have a common cellular origin.
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Uebelhoer, M., Soblet, J., Wouters, V., Mulliken, J. B., Eklund, L., Boon, L., & Vikkula, M. (2010). Somatic TIE2 mutations in sporadic venous malformations. International Vascular Biology Meeting, Los Angeles, USA. https://hdl.handle.net/2078.5/201673