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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Accession codes
References
Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000).
Lindsay, E.A. Chromosomal microdeletions: Dissecting del22q11 syndrome. Nature Rev. Genet. 2, 858–868 (2001).
Scambler, P.J. The 22q11 deletion syndromes. Hum. Mol. Genet. 9, 2421–2426 (2000).
McDermid, H.E. & Morrow, B.E. Genomic disorders on 22q11. Am. J. Hum. Genet. 70, 1077–1088 (2002).
Emanuel, B.S., McDonald-McGinn, D., Saitta, S.C. & Zackai, E.H. The 22q11.2 deletion syndrome. Adv. Pediatr. 48, 39–73 (2001).
Shprintzen, R.J. Velo-cardio-facial syndrome: A distinctive behavioral phenotype. Ment. Retard. Dev. Disabil. Res. Rev. 6, 142–147 (2000).
Driscoll, D.A. Prenatal diagnosis of the 22q11.2 deletion syndrome. Genet. Med. 3, 14–18 (2001).
Schreiber, C., Mazzitelli, D., Haehnel, J.C., Lorenz, H.P. & Meisner, H. The interrupted aortic arch: an overview after 20 years of surgical treatment. Eur. J. Cardiothorac. Surg. 12, 466–469 (1997).
Jerome, L.A. & Papaioannou, V.E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).
Lindsay, E.A. et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).
Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio- facial/DiGeorge syndrome. Cell 104, 619–629 (2001).
Gong, W. et al. Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J. Med. Genet. 38, E45 (2001).
Vitelli, F. et al. A genetic link between Tbx1 and fibroblast growth factor signaling. Development 129, 4605–4611 (2002).
Neufeld, G. et al. The neuropilins: Multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13–19 (2002).
Stalmans, I. et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327–336 (2002).
Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495–502 (1999).
Shahbazi, M. et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J. Am. Soc. Nephrol. 13, 260–264 (2002).
Awata, T. et al. A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51, 1635–1639 (2002).
Liang, D. et al. The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development. Mech. Dev. 108, 29–43 (2001).
Piotrowski, T. & Nusslein-Volhard, C. The endoderm plays an important role in patterning the segmented pharyngeal region in zebrafish (Danio rerio). Dev. Biol. 225, 339–356 (2000).
Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).
Kawasaki, T. et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895–4902 (1999).
Creazzo, T.L., Godt, R.E., Leatherbury, L., Conway, S.J. & Kirby, M.L. Role of cardiac neural crest cells in cardiovascular development. Annu. Rev. Physiol. 60, 267–286 (1998).
Srivastava, D. Genetic assembly of the heart: implications for congenital heart disease. Annu. Rev. Physiol. 63, 451–469 (2001).
Robinson, H.B., Jr. DiGeorge's or the III-IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis. Perspect. Pediatr. Pathol. 2, 173–206 (1975).
Shprintzen, R.J., Morrow, B.E. & Kucherlapati, R. Vascular anomalies may explain many of the features in velo-cardio-facial syndrome. Hum. Genet. 61 (suppl.) A5 (1997).
Mansir, T. et al. Abdominal lymphatic dysplasia and 22q11 microdeletion. Genet. Couns. 10, 67–70 (1999).
Mattot, V. et al. Loss of the VEGF164 and VEGF188 isoforms impairs postnatal glomerular angiogenesis and renal branching arteriogenesis in mice. Am. J. Soc. Nephrol. 13, 1548–1560 (2002).
Maes, C. et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF(164) and VEGF(188). Mech. Dev. 111, 61–73 (2002).
Schinzel, A.A., Smith, D.W. & Miller, J.R. Monozygotic twinning and structural defects. J. Pediatr. 95, 921–930 (1979).
Lu, J.H., Chung, M.Y., Hwang, B. & Chien, H.P. Monozygotic twins with chromosome 22q11 microdeletion and discordant phenotypes in cardiovascular patterning. Pediatr. Cardiol. 22, 260–263 (2001).
Vincent, M.C. et al. 22q11 deletion in DGS/VCFS monozygotic twins with discordant phenotypes. Genet. Couns. 10, 43–49 (1999).
Ioannidis, J.P., Ntzani, E.E., Trikalinos, T.A. & Contopoulos-Ioannidis, D.G. Replication validity of genetic association studies. Nature Genet. 29, 306–309 (2001).
Altshuler, D. et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet. 26, 76–80 (2000).
Conway, S.J., Henderson, D.J. & Copp, A.J. Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development 124, 505–514 (1997).
Conway, S.J. et al. Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc. Res. 47, 314–328 (2000).
Garg, V. et al. Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev. Biol. 235, 62–73 (2001).
Terwilliger, J.D. & Ott, J. Handbook for Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1994).
Sham, P.C. & Curtis, D. Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann. Hum. Genet. 59, 97–105 (1995).
Westerfield, M. The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio rerio) (University of Oregon Press, Eugene, 1994).
Kimmel, C.B., Ballard, W.W., Kimmel, S.R., Ullmann, B. & Schilling, T.F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253–310 (1995).
Nasevicius, A. & Ekker, S.C. Effective targeted gene 'knockdown' in zebrafish. Nature Genet. 26, 216–220 (2000).
Hauptmann, G. & Gerster, T. Two-color whole-mount in situ hybridization to vertebrate and Drosophila embryos. Trends Genet. 10, 266 (1994).
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm819
This article is cited by
-
TBX1 targets the miR-200–ZEB2 axis to induce epithelial differentiation and inhibit stem cell properties
Scientific Reports (2022)
-
Prenatal sonographic and cytogenetic/molecular findings of 22q11.2 microdeletion syndrome in 48 confirmed cases in a single tertiary center
Archives of Gynecology and Obstetrics (2022)
-
Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation
Orphanet Journal of Rare Diseases (2021)
-
Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies
Cellular and Molecular Neurobiology (2021)
-
Redox active metals in neurodegenerative diseases
JBIC Journal of Biological Inorganic Chemistry (2019)