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VEGF: A modifier of the del22q11 (DiGeorge) syndrome?

Abstract

Hemizygous 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 Vegf164-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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Figure 1: Aortic arch and conotruncal defects in Vegf120/120 and Vegf188/188 embryos and neonates.
Figure 2: Cardiac outflow defects in Vegf120/120 mice.
Figure 3: Craniofacial, thymic and parathyroid defects in Vegf120/120 neonates.
Figure 4: Expression of Vegf, Nrp1 and Tbx1 analyzed by in situ hybridization.
Figure 5: Knockdown of zebrafish vegf aggravates aortic arch artery (AAA) patterning defects in tbx1 knockdown zebrafish.

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Acknowledgements

We thank K. Brepoels, A. Bouché, E. Gils, A. Claeys, B. Hermans, L. Kieckens, W. Man, A. Manderveld, K. Maris, W. Martens, M. Nijs, S. Meynen, T. Vancoetsem, A. Vandenhoeck, K. Vandevelde, C. Van Huylebroeck, P. Van Wesemael, B. Vanwetswinkel, S. Wyns, C. Jonas and M. Trautmann for assistance; A. Kasran for performing FACS analyses; D. Anderson for providing the p75 antiserum; K. Alitalo for providing the Tie1LacZ mice and Christine Van Broeckhoven and Jurgen Del-Favero. I.S. is a Research Assistant and K.D. is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders (FWO, Belgium). D.L. is a Research Assistant of the IWT. This work is further supported by grants from the FWO (G012500), the “Research Fund K.U.Leuven Belgium” (GOA/2001/09) and the European Union (BMH4-CT98-3380), by a Bristol-Myers-Squibb grant to P.C., by a grant from Interuniversitary Attraction Poles (Belgian State) and the Belgian Foundation for Research in Paediatric Cardiology to K.D., by a grant from the British Heart Foundation to P.S., and by NIH grants (HL60714 and HL60104) to S.J.C.

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Stalmans, I., Lambrechts, D., De smet, F. et al. VEGF: A modifier of the del22q11 (DiGeorge) syndrome?. Nat Med 9, 173–182 (2003). https://doi.org/10.1038/nm819

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