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

N Limaye, V Wouters, M Uebelhoer, M Tuominen… - Nature …, 2009 - nature.com
N Limaye, V Wouters, M Uebelhoer, M Tuominen, R Wirkkala, JB Mulliken, L Eklund…
Nature genetics, 2009nature.com
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malformation (VMCM; refs.,, and VW, NL, MU, A. Irrthum, LMB et al., unpublished data).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 …
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. , , and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data).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.
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