Letter | Published:

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

Naturevolume 427pages640645 (2004) | Download Citation



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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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..

Author information

Author notes

    • Julian Borrow

    Present address: Cancer Research UK, Leukemia Molecular Genetics, Paterson Institute for Cancer Research, Manchester, M20 4BX, UK

  1. Xiao-Li Tian, Rajkumar Kadaba, Sun-Ah You and Mugen Liu: These authors contributed equally to this work


  1. Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute

    • Xiao-Li Tian
    • , Rajkumar Kadaba
    • , Sun-Ah You
    • , Mugen Liu
    • , Ayse Anil Timur
    • , Shaoqi Rao
    • , Ling Wu
    •  & Qing Wang
  2. Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation

    • Xiao-Li Tian
    • , Rajkumar Kadaba
    • , Sun-Ah You
    • , Mugen Liu
    • , Ayse Anil Timur
    • , Shaoqi Rao
    • , Ling Wu
    •  & Qing Wang
  3. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, 44195, USA

    • Xiao-Li Tian
    • , Rajkumar Kadaba
    • , Sun-Ah You
    • , Mugen Liu
    • , Ayse Anil Timur
    • , Shaoqi Rao
    • , Ling Wu
    •  & Qing Wang
  4. Institute of Genetics, Fudan University, 200433, Shanghai, China

    • Mugen Liu
  5. Department of Cell Biology, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

    • Lin Yang
    •  & Paul E. DiCorleto
  6. Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

    • Qiuyun Chen
  7. Department of Pathology, Baylor College of Medicine, Houston, Texas, 77030, USA

    • Przemyslaw Szafranski
  8. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    • David E. Housman
    •  & Julian Borrow
  9. Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, 55905, USA

    • David J. Driscoll


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The authors declare that they have no competing financial interests.

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Correspondence to Qing Wang.

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