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

Xiao-Li Tian, Rajkumar Kadaba, Sun-Ah You, Mugen Liu, Ayse Anil Timur, Lin Yang, Qiuyun Chen, Przemyslaw Szafranski, Shaoqi Rao, Ling Wu, David E. Housman, Paul E. DiCorleto, David J. Driscoll, Julian Borrow and Qing Wang ()
Additional contact information
Xiao-Li Tian: Lerner Research Institute
Rajkumar Kadaba: Lerner Research Institute
Sun-Ah You: Lerner Research Institute
Mugen Liu: Lerner Research Institute
Ayse Anil Timur: Lerner Research Institute
Lin Yang: The Cleveland Clinic Foundation
Qiuyun Chen: Cole Eye Institute, The Cleveland Clinic Foundation
Przemyslaw Szafranski: Baylor College of Medicine
Shaoqi Rao: Lerner Research Institute
Ling Wu: Lerner Research Institute
David E. Housman: Massachusetts Institute of Technology
Paul E. DiCorleto: The Cleveland Clinic Foundation
David J. Driscoll: Mayo Clinic
Julian Borrow: Massachusetts Institute of Technology
Qing Wang: Lerner Research Institute

Nature, 2004, vol. 427, issue 6975, 640-645

Abstract: 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.

Date: 2004
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DOI: 10.1038/nature02320

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