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

Naturevolume 427pages640645 (2004) | Download Citation

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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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References

  1. 1

    Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000)

  2. 2

    Berry, S. A. et al. Klippel–Trenaunay syndrome. Am. J. Med. Genet. 79, 319–326 (1998)

  3. 3

    Jacob, A. G. et al. Klippel–Trenaunay syndrome: spectrum and management. Mayo Clin. Proc. 73, 28–36 (1998)

  4. 4

    Wiley, S. R. et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 15, 837–846 (2001)

  5. 5

    Lynch, C. N. et al. TWEAK induces angiogenesis and proliferation of endothelial cells. J. Biol. Chem. 274, 8455–8459 (1999)

  6. 6

    Buschmann, I. & Schaper, W. Arteriogenesis versus angiogenesis: Two mechanisms of vessel growth. News Physiol. Sci. 14, 121–125 (1999)

  7. 7

    Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000)

  8. 8

    Folkman, J. & D'Amore, P. A. Blood vessel formation: what is its molecular basis? Cell 87, 1153–1155 (1996)

  9. 9

    Risau, W. Mechanisms of angiogenesis. Nature 386, 671–674 (1997)

  10. 10

    Whelan, A. J., Watson, M. S., Porter, F. D. & Steiner, R. D. Klippel–Trenaunay–Weber syndrome associated with a 5:11 balanced translocation. Am. J. Med. Genet. 59, 492–494 (1995)

  11. 11

    Durocher, D., Henckel, J., Fersht, A. R. & Jackson, S. P. The FHA domain is a modular phosphopeptide recognition motif. Mol. Cell 4, 387–394 (1999)

  12. 12

    Guglielmi, B. & Werner, M. The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition. J. Biol. Chem. 277, 35712–35719 (2002)

  13. 13

    Hoggart, C. J. et al. Control of confounding of genetic associations in stratified populations. Am. J. Hum. Genet. 72, 1492–1504 (2003)

  14. 14

    Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001)

  15. 15

    Shriver, M. D. et al. Ethnic-affiliation estimation by use of population-specific DNA markers. Am. J. Hum. Genet. 60, 957–964 (1997)

  16. 16

    Barker, D., Schafer, M. & White, R. Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 36, 131–138 (1984)

  17. 17

    Pfeffer, S. Membrane domains in the secretory and endocytic pathways. Cell 112, 507–517 (2003)

  18. 18

    Mignatti, P., Morimoto, T. & Rifkin, D. B. Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J. Cell. Physiol. 151, 81–93 (1992)

  19. 19

    Calvert, J. T. et al. Allelic and locus heterogeneity in inherited venous malformations. Hum. Mol. Genet. 8, 1279–1289 (1999)

  20. 20

    Baskerville, P. A., Ackroyd, J. S. & Browse, N. L. The etiology of the Klippel–Trenaunay syndrome. Ann. Surg. 202, 624–627 (1985)

  21. 21

    Wiley, S. R. & Winkles, J. A. TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine Growth Factor Rev. 14, 241–249 (2003)

  22. 22

    Wang, Q. et al. Identification and molecular characterization of de novo translocation t(8;14)(q22.3;q13) associated with a vascular and tissue overgrowth syndrome. Cytogenet. Cell Genet. 95, 183–188 (2001)

  23. 23

    Happle, R. Klippel–Trenaunay syndrome: is it a paradominant trait? Br. J. Dermatol. 128, 465–466 (1993)

  24. 24

    Jackson, C. L., et al. in Current Protocols in Human Genetics (ed. Dracopoli, N. C.) 3.2.1–3.2.29 (Wiley, New York, 1996)

  25. 25

    Chen, Q. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392, 293–296 (1998)

  26. 26

    Wang, Q. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995)

  27. 27

    Wang, L., Fan, C., Topol, S. E., Topol, E. J. & Wang, Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302, 1578–1581 (2003)

  28. 28

    Fan, C., Liu, M. & Wang, Q. Functional analysis of TBX5 missense mutations associated with Holt–Oram syndrome. J. Biol. Chem. 278, 8780–8785 (2003)

  29. 29

    Fan, C. et al. Novel TBX5 mutations and molecular mechanism for Holt–Oram syndrome. J. Med. Genet. 40, e29 (2003)

  30. 30

    Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599–611 (2002)

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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..

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

Affiliations

  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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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Qing Wang.

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https://doi.org/10.1038/nature02320

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