Abstract
Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.
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Acknowledgements
We are grateful to all the families for their participation in this study. We thank Antonella Mendola for her expert technical assistance and Liliana Niculescu for secretarial help. This study was partially supported by the Interuniversity Attraction Poles initiated by the Belgian Federal Science Policy, network 5/25 and 6/05; Concerted Research Actions (A.R.C.)—Convention No 02/07/276 and 7/12-005 of the Belgian French Community Ministry; the National Institute of Health, Program Project P01 AR048564; EU FW6 Integrated project LYMPHANGIOGENOMICS, LSHG-CT-2004-503573 and the F.N.R.S. (Fonds national de la recherche scientifique) (to MV, a ‘Maître de recherches honoraire du F.N.R.S.’); and by a fellowship from F.R.I.A. (Fonds pour la formation à la recherche dans l’industrie et dans l’agriculture), and Patrimoine UCL (to VW).
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Wouters, V., Limaye, N., Uebelhoer, M. et al. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet 18, 414–420 (2010). https://doi.org/10.1038/ejhg.2009.193
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DOI: https://doi.org/10.1038/ejhg.2009.193
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