Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects
Por:
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
Publicada:
1 abr 2010
Resumen:
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
Filiaciones:
Wouters, V:
Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Lab Human Mol Genet, B-1200 Brussels, Belgium
Limaye, N:
Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Lab Human Mol Genet, B-1200 Brussels, Belgium
Uebelhoer, M:
Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Lab Human Mol Genet, B-1200 Brussels, Belgium
Irrthum, A:
Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Lab Human Mol Genet, B-1200 Brussels, Belgium
Boon, LM:
Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Lab Human Mol Genet, B-1200 Brussels, Belgium
Univ Catholique Louvain, Clin Univ St Luc, Ctr Vasc Anomalies, Div Plast Surg, B-1200 Brussels, Belgium
Mulliken, JB:
Childrens Hosp, Vasc Anomalies Ctr, Boston, MA 02115 USA
Enjolras, O:
Hop Lariboisiere, F-75475 Paris, France
Baselga, E:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Berg, J:
Kings Coll London, Guys Hosp, GKT Sch Med, Div Med & Mol Genet, London WC2R 2LS, England
Dompmartin, A:
CHU Caen, Dept Dermatol, F-14000 Caen, France
Ivarsson, SA:
Univ Sjukhuset, Barnkliniken, Malmo, Sweden
Lacassie, Y:
LSU Hlth Sci Ctr, Dept Pediat, Div Genet, New Orleans, LA USA
Childrens Hosp, New Orleans, LA USA
Murphy, J:
Hosp Sick Children, Toronto, ON M5G 1X8, Canada
Teebi, AS:
Hosp Sick Children, Toronto, ON M5G 1X8, Canada
Penington, A:
Univ Melbourne, St Vincents Hosp, Dept Surg, Melbourne, Vic 3010, Australia
Rieu, P:
Univ Nijmegen, UMC, St Rabdoud, Netherlands
Vikkula, M:
Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Lab Human Mol Genet, B-1200 Brussels, Belgium
Bronze, Green Accepted, Green Published
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