Nature Medicine
9, 173 - 182 (2003)
Published online: 21 January 2003; | doi:10.1038/nm819
VEGF: A modifier of the del22q11 (DiGeorge) syndrome?Ingeborg Stalmans1, 12, Diether Lambrechts1, 12, Frederik De smet1, Sandra Jansen1, Jian Wang5, Sunit Maity1, 6, Paige Kneer5, Maren von der Ohe6, Ann Swillen2, Christa Maes3, Marc Gewillig4, Daniel G.M. Molin7, Peter Hellings1, Thurid Boetel6, Maartin Haardt6, Veerle Compernolle1, Mieke Dewerchin1, Stephane Plaisance1, Robert Vlietinck2, 8, Beverly Emanuel9, Adriana C. Gittenberger-de Groot7, Peter Scambler10, Bernice Morrow11, Deborah A. Driscol9, Lieve Moons1, Camila V. Esguerra1, 6, Geert Carmeliet3, Annett Behn-Krappa6, Koen Devriendt2, Désiré Collen1, Simon J. Conway5
& Peter Carmeliet11
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium
2
The Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium
3
Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
4
Department of Pediatrics, Katholieke Universiteit Leuven, Leuven, Belgium
5
Institute of Molecular Medicine & Genetics, Medical College of Georgia, Augusta, Georgia, USA
6
Mermaid Pharmaceuticals GmbH, Falkenried 88 (CiM), Hamburg, Germany
7
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
8
Department of Population Genetics, Genomics & Bioinformatics, University Maastricht, Maastricht, The Netherlands
9
Division of Reproductive Genetics, Department of Obstetrics & Gynecology, Division of Human Genetics & Molecular Biology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
10
Molecular Medicine Unit, Institute of Child Health, London, UK
11
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, USA
12
I.S. and D.L. contributed equally to this study.
Correspondence should be addressed to Simon J. Conway sconway@mail.mcg.edu or Peter Carmeliet peter.carmeliet@med.kuleuven.ac.beHemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf
164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.
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