Vascular malformations are most often caused by somatic mutations of the PI3K/mTOR and the RAS signaling pathways, which can be identified in the affected tissue. Venous malformations commonly harbor PIK3CA and TEK mutations, whereas arteriovenous malformations are usually caused by BRAF, RAS, or MAP2K1 mutations. Correct identification of the underlying mutation is of increasing importance, since targeted treatments are becoming more and more relevant, especially in patients with extensive vascular malformations. However, variants of unknown significance are often identified and their pathogenicity and response to targeted therapy cannot be precisely predicted. Here we show, that zebrafish embryos can be used to rapidly assess the pathogenicity of novel variants of unknown significance in TEK, encoding for the receptor TIE2, present on endothelial cells of venous malformations. Endothelium-specific overexpression of TEK mutations leads to robust induction of venous malformations whereas MAP2K1 mutations cause arteriovenous malformations in our zebrafish model. TEK mutations are often found as double mutations in cis; using our model, we show that double mutations have an additive effect in inducing venous malformations compared to the respective single variants. The clinically established mTOR-inhibitor sirolimus (rapamycin) efficiently abrogates the development of venous malformations in this zebrafish model. In summary, endothelium-specific overexpression of patient-derived TEK variants in the zebrafish model allows assessment of their pathogenic significance as well as testing of candidate drugs in a personalized and mutation-specific approach.
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