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known as a mucocutaneous venous malformation (VMCM; refs. 1, 2, 3 and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data).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

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Figure 1: Somatic deletion in Ig2 extracellular domain in a VMCM.
Figure 2: Del-TIE2 is retained in the endoplasmic reticulum (ER).
Figure 3: Typical features of sporadic venous malformations.
Figure 4: Somatic TEK mutations identified in sporadic venous malformation tissues cause ligand-independent hyperphosphorylation.
Figure 5: Ang1-induced TIE2 clustering and phosphorylation in HUVECs expressing mutant (R849W and L914F) and wild-type (WT) TIE2.
Figure 6: Cellular localization and activation of L914F-TIE2.

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Acknowledgements

We thank the patients for their invaluable contributions; A. Mendola, A. Van Egeren and J. Träskelin for expert technical assistance; C. Godfraind for immunohistochemistry; and L. Niculescu for secretarial help. These studies were partially supported by the Interuniversity Attraction Poles initiated by the Belgian Federal Science Policy (network 5/25 and 6/05), Concerted Research Actions (ARC) Conventions no. 02/07/276 and 7/12-005 of the Belgian French Community Ministry, National Institutes of Health program project P01 AR048564-01A1, EU FW6 Integrated Project LYMPHANGIOGENOMICS (LSHG-CT-2004-503573), the Fonds national de la recherche scientifique (to M.V., a 'Maître de recherches du FNRS'); a fellowship from Fonds pour la formation à la recherche dans l'industrie et dans l'agriculture (to V.W.), the Patrimoine UCL and the Academy of Finland (116138 to L.E. and M.T.).

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Contributions

L.E. and M.V. participated in experimental design, data analysis and writing; N.L., V.W. and L.E. participated in experimental design, data collection and analysis, writing and figure processing; M.U. contributed significantly to data collection and figure processing; M.T. contributed significantly to data collection, analysis, figure processing and writing and planning of experiments; R.W. contributed to data collection; and J.B.M. and L.M.B. provided clinical expertise, patient recruitment and detailed clinical descriptions. M.U. and M.T. contributed equally.

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Correspondence to Miikka Vikkula.

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Supplementary Figures 1–5, Supplementary Tables 1–3 and Supplementary Methods (PDF 3249 kb)

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Limaye, N., Wouters, V., Uebelhoer, M. et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet 41, 118–124 (2009). https://doi.org/10.1038/ng.272

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