Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects

Vinciane Wouters; Nisha Limaye; Melanie Uebelhoer; Alexandre Irrthum; Laurence M. Boon; John B. Mulliken; Odile Enjolras; Eulalia Baselga; Jonathan Berg; Anne Dompmartin; Sten A. Ivarsson; Loshan Kangesu; Yves Lacassie; Jill Murphy; Ahmad S. Teebi; Anthony Penington; Paul Rieu; Miikka Vikkula

doi:10.1038/ejhg.2009.193

Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects

Vinciane Wouters, Nisha Limaye, Melanie Uebelhoer, Alexandre Irrthum, Laurence M. Boon, John B. Mulliken, Odile Enjolras, Eulalia Baselga, Jonathan Berg, Anne Dompmartin, Sten A. Ivarsson, Loshan Kangesu, Yves Lacassie, Jill Murphy, Ahmad S. Teebi, Anthony Penington, Paul Rieu, Miikka Vikkula

King's College London

Research output: Contribution to journal › Article › peer-review

133 Citations (Scopus)

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. European Journal of Human Genetics (2010) 18, 414-420; doi:10.1038/ejhg.2009.193; published online 4 November 2009

Original language	English
Pages (from-to)	414 - 420
Number of pages	7
Journal	European Journal of Human Genetics
Volume	18
Issue number	4
DOIs	https://doi.org/10.1038/ejhg.2009.193
Publication status	Published - Apr 2010

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Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., & Vikkula, M. (2010). Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. European Journal of Human Genetics, 18(4), 414 - 420. https://doi.org/10.1038/ejhg.2009.193

@article{bf944c0fe95e4b34bcd4dcba570be686,

title = "Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects",

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. European Journal of Human Genetics (2010) 18, 414-420; doi:10.1038/ejhg.2009.193; published online 4 November 2009",

author = "Vinciane Wouters and Nisha Limaye and Melanie Uebelhoer and Alexandre Irrthum and Boon, {Laurence M.} and Mulliken, {John B.} and Odile Enjolras and Eulalia Baselga and Jonathan Berg and Anne Dompmartin and Ivarsson, {Sten A.} and Loshan Kangesu and Yves Lacassie and Jill Murphy and Teebi, {Ahmad S.} and Anthony Penington and Paul Rieu and Miikka Vikkula",

year = "2010",

month = apr,

doi = "10.1038/ejhg.2009.193",

language = "English",

volume = "18",

pages = "414 -- 420",

journal = "European Journal of Human Genetics",

publisher = "Nature Publishing Group",

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Wouters, V, Limaye, N, Uebelhoer, M, Irrthum, A, Boon, LM, Mulliken, JB, Enjolras, O, Baselga, E, Berg, J, Dompmartin, A, Ivarsson, SA, Kangesu, L, Lacassie, Y, Murphy, J, Teebi, AS, Penington, A, Rieu, P & Vikkula, M 2010, 'Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects', European Journal of Human Genetics, vol. 18, no. 4, pp. 414 - 420. https://doi.org/10.1038/ejhg.2009.193

TY - JOUR

T1 - Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects

AU - Wouters, Vinciane

AU - Limaye, Nisha

AU - Uebelhoer, Melanie

AU - Irrthum, Alexandre

AU - Boon, Laurence M.

AU - Mulliken, John B.

AU - Enjolras, Odile

AU - Baselga, Eulalia

AU - Berg, Jonathan

AU - Dompmartin, Anne

AU - Ivarsson, Sten A.

AU - Kangesu, Loshan

AU - Lacassie, Yves

AU - Murphy, Jill

AU - Teebi, Ahmad S.

AU - Penington, Anthony

AU - Rieu, Paul

AU - Vikkula, Miikka

PY - 2010/4

Y1 - 2010/4

N2 - 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. European Journal of Human Genetics (2010) 18, 414-420; doi:10.1038/ejhg.2009.193; published online 4 November 2009

AB - 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. European Journal of Human Genetics (2010) 18, 414-420; doi:10.1038/ejhg.2009.193; published online 4 November 2009

U2 - 10.1038/ejhg.2009.193

DO - 10.1038/ejhg.2009.193

M3 - Article

VL - 18

SP - 414

EP - 420

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 4

ER -

Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects

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