title: Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.
abstract: 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known as a mucocutaneous venous malformation (VMCM; refs. 1, 2, 3 and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data).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.
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nisha
authors.initials: N
authors.lastname: Limaye
authors.forename: Vinciane
authors.initials: V
authors.lastname: Wouters
authors.forename: Melanie
authors.initials: M
authors.lastname: Uebelhoer
authors.forename: Marjut
authors.initials: M
authors.lastname: Tuominen
authors.forename: Riikka
authors.initials: R
authors.lastname: Wirkkala
authors.forename: John B
authors.initials: JB
authors.lastname: Mulliken
authors.forename: Lauri
authors.initials: L
authors.lastname: Eklund
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Boon
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000737:chemistry / Q000235:genetics*; D017384:Sequence Deletion; D054079:Vascular Malformations / Q000235:genetics*
chemical_list: D042683:Angiopoietin-1; D008024:Ligands; D050505:Mutant Proteins; D042787:Receptor, TIE-2