Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations

Nisha Limaye, Vinciane Wouters, Melanie Uebelhoer, Marjut Tuominen, Riikka Wirkkala, John B. Mulliken, Lauri Eklund, Laurence M. Boon, Miikka Vikkula*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

230 Scopus citations


Germline substitutions in the endothelial cell tyrosine kinase receptor TIE2 (encoded by TEK) cause a rare, inherited form of venous anomaly known as a mucocutaneous venous malformation (VMCM; refs. 1, 2, 3 and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data). We identified a somatic 'second hit' causing loss of function of TIE2 in a resected VMCM and assessed whether such localized, tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common. We identified eight somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations; the mutations were absent from the individuals' blood and control tissues. The somatic mutations included one causing a frequent L914F substitution and several double mutations in cis, all of which resulted in ligand-independent TIE2 hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wild-type TIE2 and the common, inherited R849W mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in two individuals suggests a common origin for the abnormal endothelial cells at the distant sites. These data show 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 venous malformations.

Original languageEnglish (US)
Pages (from-to)118-124
Number of pages7
JournalNature Genetics
Issue number1
StatePublished - Jan 2009
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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