1. Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, and Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA
2. Institute of Genetics, Fudan University, Shanghai 200433, China
3. Department of Cell Biology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
4. Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
5. Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA
6. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
7. Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota 55905, USA
8. These authors contributed equally to this work
9. Present address: Cancer Research UK, Leukemia Molecular Genetics, Paterson Institute for Cancer Research, Manchester, M20 4BX, UK

Correspondence to: Qing Wang¹ Email: wangq2@ccf.org
The GenBank accession numbers are AY500994 for human VG5Q (hVG5Q) mRNA and amino acid sequences; AY500995 for mouse VG5Q (mVG5Q) mRNA and amino acid sequences; and AY500996 for human VG5Q genomic DNA sequence.

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.

1. Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, and Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA
2. Institute of Genetics, Fudan University, Shanghai 200433, China
3. Department of Cell Biology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
4. Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
5. Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA
6. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
7. Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota 55905, USA
8. These authors contributed equally to this work
9. Present address: Cancer Research UK, Leukemia Molecular Genetics, Paterson Institute for Cancer Research, Manchester, M20 4BX, UK

Correspondence to: Qing Wang¹ Email: wangq2@ccf.org
The GenBank accession numbers are AY500994 for human VG5Q (hVG5Q) mRNA and amino acid sequences; AY500995 for mouse VG5Q (mVG5Q) mRNA and amino acid sequences; and AY500996 for human VG5Q genomic DNA sequence.

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