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Identification of an angiogenic factor that when mutated causes susceptibility to Klippel–Trenaunay syndrome

Abstract

Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network1. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel–Trenaunay syndrome (KTS)2,3. One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12)4,5. These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.

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Figure 1: Positional cloning of the VG5Q gene.
Figure 2: Expression profile of VG5Q and dynamic redistribution and secretion of VG5Q protein during angiogenesis.
Figure 3: VG5Q is an angiogenic factor and both VG5Q E133K and KTS translocation t(5;11) are functional mutations.
Figure 4: VG5Q interacts with TWEAK.

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Acknowledgements

We thank E. Plow for critical reading of the manuscript; H. Yagita for plasmid hTWEAK/pCR3.1; S. Chen, M. K. Cathcart, A. Sadgephour, Z. Tang, C. Fan, P. B. Imrey, S. Archacki, D. Kikta, J. Poruban and A. Moore for help; and KTS patients for their participation in this study. This work was supported by NIH grants to Q.W..

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Correspondence to Qing Wang.

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Tian, XL., Kadaba, R., You, SA. et al. Identification of an angiogenic factor that when mutated causes susceptibility to Klippel–Trenaunay syndrome. Nature 427, 640–645 (2004). https://doi.org/10.1038/nature02320

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