Various activating TIE2 tyrosine kinase domain mutations, including the recurrent R849W substitution, cause cutaneomucosal venous malformation (VMCM) in a paradominant fashion

Venous malformations are the most frequent vascular anomalies among patients in specialized centers, characterized by localized bluish lesions in the skin and the mucosae. While these are predominantly sporadic in nature, 1 to 2% occur as an autosomal dominantly inherited trait termed cutaneomucosal venous malformation (VMCM). The angiopoeitin receptor TIE2 has been identified as the causative gene for VMCM in five families. In each family, one of two specific substitutions (R849W or Y897S) in the kinase domain of TIE2 co-segregates with the disorder. These mutations result in increased ligand-independant phosphorylation of the receptor, and altered downstream signaling. Here, we studied twelve new families with VMCM: six bear the R849W substitution, five have a novel mutation in the tyrosine kinase domain and one in the carboxy-terminal end of the receptor. Overexpression of each of these mutants in COS-7 cells resulted in ligand independent hyper-phosphorylation of the receptor, suggesting that this is a general feature of VMCM-causing TIE2 mutations. Interestingly, we also discovered a somatic deletion in a resected VM tissue sample from one patient with the inherited R849W mutation. This somatic alteration partially deletes the ligand binding domain of the receptor in the allele that does not bear the R849W mutation. This is the first report of a double-hit mutation in VMCM. Moreover, we demonstrate that the somatic deletion does not result in hyper-phosphorylation, nor does it cause an increase in the phosphorylation of the R849W allele. Thus, this deletion rather seems to cause an elimination of the wild-type allele that is able to protect from the deleterious effects of the mutant, inherited allele. In conclusion, the focal development of VMCM is likely due to the combination of various predisposing germline mutations that cause hyperphosphorylation of the receptor, and a somatic second-hit, hallmarks of paradominant inheritance. (miikka.vikkula@uclouvain.be)