論文 - 詳細
| RRC ID | 85210 |
|---|---|
| 著者 | Bell LM, Holm A, Matysiak U, Driever W, Rößler J, Schanze D, Wieland I, Niemeyer CM, Zenker M, Kapp FG. |
| タイトル | Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos. |
| ジャーナル | Hum Mol Genet |
| Abstract |
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 (VMs) commonly harbor PIK3CA and TEK mutations, whereas arteriovenous malformations (AVMs) 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 (VUSs) 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 VUSs in TEK, encoding for the receptor TIE2, present on endothelial cells of VMs. Endothelium-specific overexpression of TEK mutations leads to robust induction of VMs, whereas MAP2K1 mutations cause AVMs 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 VMs compared with the respective single variants. The clinically established mTOR-inhibitor sirolimus (rapamycin) efficiently abrogates the development of VMs 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. |
| 巻・号 | 31(1) |
| ページ | 10-17 |
| 公開日 | 2021-12-17 |
| DOI | 10.1093/hmg/ddab196 |
| PII | 6319590 |
| PMID | 34254124 |
| MeSH | Animals Endothelial Cells / metabolism Endothelium / metabolism Endothelium / pathology Humans Mutation Receptor, TIE-2* / genetics Vascular Malformations* / genetics Zebrafish* / genetics Zebrafish* / metabolism |
| IF | 5.101 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | UAS:RFP |