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 4-fold 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 novel, 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 novel 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, 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.

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

“…Although the TEK FN3 crystal structure is currently unavailable, the lack of membrane response following ANGPT1 stimulation as observed in HUVECs ( Figure 3A) is likely due to impaired signaling activities. GoF mutations in patients with VMs exhibit variable expressivity and led to the hypothesis that tight regulation of TEK activity is needed for vascular development (34,54). Our findings that hemizygosity for Tek is sufficient to cause disease in mice and that heterozygosity for LoF mutations is associated with PCG of varying severity in patients suggest, for the first time to our knowledge, that there exists a dosage sensitivity for reduced activity of the receptor.…”

“…Measurement of IOP confirmed that haploinsufficient mice exhibited a 25% elevation in IOP (control 12.3 gain-of-function (GoF) TEK mutations that have been linked with hereditary and sporadic venous malformations (VMs) (34,53,54). These VM mutations are located solely in the intracellular domain and result in enhanced kinase activity.…”

“…50% reduction of the signal leads to severely hypomorphic SC formation with elevated IOP in mice, and PCG in humans with variable expressivity. In human patients, GoF mutations in TEK result in VMs in nonocular tissues (34,53,54 (65) to analyze whether the variants can cause changes in splice sites. Detailed protocols are available in the Supplemental Material.…”

Arteriovenous Malformations and Other Vascular Malformation Syndromes

“…VMs are the result of local aberrations in angiogenesis occurring in fetal development and can range in clinical spectrum from benign cosmetic varicosities to multifocal lesions in multiple vital organs (Brouillard and Vikkula 2003;Wouters et al 2009). The majority of vascular malformations have no known genetic component and are sporadic in nature.…”

“…However, families with dominant inheritance of VMs have been identified, and linkage analysis has localized mutations in the TEK gene on chromosome 9p21. This gene codes for the angiopoietin-1 receptor protein Tie2, and the majority of mutations identified thus far have been in or near the amino-terminal-most of two kinase domains within the intracellular portion of the protein (Wouters et al 2009). These autosomal-dominant venous malformations termed cutaneomucosal venous malformations (VMCMs) tend to involve small multifocal mucocutaneous lesions in addition to the possibility of other venous malformations.…”