Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.
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.
Wouters
Vinciane
V
Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, Belgium.
Limaye
Nisha
N
Uebelhoer
Melanie
M
Irrthum
Alexandre
A
Boon
Laurence M
LM
Mulliken
John B
JB
Enjolras
Odile
O
Baselga
Eulalia
E
Berg
Jonathan
J
Dompmartin
Anne
A
Ivarsson
Sten A
SA
Kangesu
Loshan
L
Lacassie
Yves
Y
Murphy
Jill
J
Teebi
Ahmad S
AS
Penington
Anthony
A
Rieu
Paul
P
Vikkula
Miikka
M
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006239:Haplotypes; D006801:Humans; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009059:Mouth Diseases / Q000235:genetics* / Q000473:pathology; D009061:Mouth Mucosa / Q000098:blood supply; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply; D012871:Skin Diseases / Q000235:genetics* / Q000473:pathology; D054079:Vascular Malformations / Q000235:genetics* / Q000473:pathology; D014680:Veins
D008024:Ligands; D012333:RNA, Messenger; D042787:Receptor, TIE-2