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

Nat Genet. 2009 Jan;41(1):118-24. doi: 10.1038/ng.272. Epub 2008 Dec 14.


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known as a mucocutaneous venous malformation (VMCM; refs. 1, 2, 3 and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data).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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1 / pharmacology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Humans
  • Ligands
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Phosphorylation / drug effects
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • Receptor, TIE-2 / chemistry
  • Receptor, TIE-2 / genetics*
  • Sequence Deletion
  • Vascular Malformations / genetics*


  • Angiopoietin-1
  • Ligands
  • Mutant Proteins
  • Receptor, TIE-2

Associated data

  • OMIM/#600195
  • OMIM/600221
  • RefSeq/NM_000459