Abstract
Neural tube defects (NTDs), including anencephaly and spina bifida, are multifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom1. Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor α-receptor (Pdgfra) causes congenital NTDs (refs. 2–4), whereas mutant forms of Pax-1 that have been associated with NTDs cause deregulated activation of the human PDGFRA promoter2,5. There is an increasing awareness that genetic polymorphisms may have an important role in the susceptibility for NTDs (ref. 6). Here we identify five different haplotypes in the human PDGFRA promoter, of which the two most abundant ones, designated H1 and H2α, differ in at least six polymorphic sites. In a transient transfection assay in human bone cells, the five haplotypes differ strongly in their ability to enhance reporter gene activity. In a group of patients with sporadic spina bifida, haplotypes with low transcriptional activity, including H1, were under-represented, whereas those with high transcriptional activity, including H2α, were over-represented. When testing for haplotype combinations, H1 homozygotes were fully absent from the group of sporadic patients, whereas H1/H2α heterozygotes were over-represented in the groups of both sporadic and familial spina bifida patients, but strongly under-represented in unrelated controls. Our data indicate that specific combinations of naturally occurring PDGFRA promoter haplotypes strongly affect NTD genesis.
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
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dolk, H. et al. Heterogeneity of neural tube defects in Europe: the significance of site of defect and presence of other major anomalies in relation to geographic differences in prevalence. Teratology 44, 547–559 (1991).
Helwig, U. et al. Interaction between undulated and Patch leads to an extreme form of spina bifida in double-mutant mice. Nature Genet. 11, 60–63 (1995).
Payne, J., Shibasaki, F. & Mercola, M. Spina bifida occulta in homozygous Patch mouse embryos. Dev. Dyn. 209, 105–116 (1997).
Soriano, P. The PDGF α receptor is required for neural crest cell development and for normal patterning of the somites. Development 124, 2691–2700 (1997).
Joosten, P.H. et al. Altered regulation of platelet-derived growth factor receptor-α gene-transcription in vitro by spina bifida-associated mutant Pax1 proteins. Proc. Natl. Acad. Sci. USA 95, 14459–14463 (1998).
Fleming, A. & Copp, A.J. A genetic risk factor for mouse neural tube defects: defining the embryonic basis. Hum. Mol. Genet. 9, 575–581 (2000).
Afink, G.B. et al. Molecular cloning and functional characterization of the human platelet-derived growth factor α receptor gene promoter. Oncogene 10, 1667–1672 (1995).
Zhang, X.Q. et al. Specific expression in mouse mesoderm- and neural crest-derived tissues of a human PDGFRA promoter/lacZ transgene. Mech. Dev. 70, 167–180 (1998).
Herrmann, S.M. et al. Polymorphisms in the genes encoding platelet-derived growth factor A and α receptor. J. Mol. Med. 78, 287–292 (2000).
Peters, H. et al. Pax1 and Pax9 synergistically regulate vertebral column development. Development 126, 5399–5408 (1999).
Wallin, J. et al. The role of Pax-1 in axial skeleton development. Development 120, 1109–1121 (1994).
Campbell, L.R., Dayton, D.H. & Sohal, G.S. Neural tube defects: a review of human and animal studies on the etiology of neural tube defects. Teratology 34, 171–187 (1986).
Barber, R.C. et al. Lack of association between mutations in the folate receptor-α gene and spina bifida. Am. J. Med. Genet. 76, 310–317 (1998).
Barber, R.C., Lammer, E.J., Shaw, G.M., Greer, K.A. & Finnell, R.H. The role of folate transport and metabolism in neural tube defect risk. Mol. Genet. Metab. 66, 1–9 (1999).
Copp, A.J. & Bernfield, M. Etiology and pathogenesis of human neural tube defects: insights from mouse models. Curr. Opin. Pediatr. 6, 624–631 (1994).
Boone, D., Parsons, D., Lachmann, S.M. & Sherwood, T. Spina bifida occulta: lesion or anomaly? Clin. Radiol. 36, 159–161 (1985).
Fidas, A. et al. Prevalence and patterns of spina bifida occulta in 2707 normal adults. Clin. Radiol. 38, 537–542 (1987).
Hol, F.A. et al. PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida. J. Med. Genet. 33, 655–660 (1996).
Kondo, T. & Raff, M. The Id4 HLH protein and the timing of oligodendrocyte differentiation. EMBO J. 19, 1998–2007 (2000).
Shimizu-Nishikawa, K., Tazawa, I., Uchiyama, K. & Yoshizato, K. Expression of helix-loop-helix type negative regulators of differentiation during limb regeneration in urodeles and anurans. Dev. Growth Differ. 41, 731–743 (1999).
Drysdale, C.M. et al. Complex promoter and coding region β 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc. Natl. Acad. Sci. USA 97, 10483–10488 (2000).
Wang, C. & Song, B. Cell-type-specific expression of the platelet-derived growth factor α receptor: a role for GATA-binding protein. Mol. Cell. Biol. 16, 712–723 (1996).
Epstein, J.A., Song, B., Lakkis, M. & Wang, C. Tumor-specific PAX3-FKHR transcription factor, but not PAX3, activates the platelet-derived growth factor alpha receptor. Mol. Cell. Biol. 18, 4118–4130 (1998).
Fukuoka, T., Kitami, Y., Okura, T. & Hiwada, K. Transcriptional regulation of the platelet-derived growth factor α receptor gene via CCAAT/enhancer-binding protein-δ in vascular smooth muscle cells. J. Biol. Chem. 274, 25576–25582 (1999).
Pirrotta, V. Transvection and chromosomal trans-interaction effects. Biochim. Biophys. Acta 1424, M1–M8 (1999).
Ashe, H.L., Monks, J., Wijgerde, M., Fraser, P. & Proudfoot, N.J. Intergenic transcription and transinduction of the human β-globin locus. Genes Dev. 11, 2494–2509 (1997).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Plainview, NY, 1989).
Rousset, F. & Raymond, M. Testing heterozygote excess and deficiency. Genetics 140, 1413–1419 (1995).
Acknowledgements
We thank F. Hol, B. Franke, D. van Oosterhout and B. Hamel for contributions; and J. Ouborg for statistical advice. This study was supported by the Dutch Prinses Beatrix fonds.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Joosten, P., Toepoel, M., Mariman, E. et al. Promoter haplotype combinations of the platelet-derived growth factor α-receptor gene predispose to human neural tube defects. Nat Genet 27, 215–217 (2001). https://doi.org/10.1038/84867
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/84867
This article is cited by
-
Distinct DNA methylation profiles in subtypes of orofacial cleft
Clinical Epigenetics (2017)
-
Lack of association between −174G>C and −634C>G polymorphisms in interleukin-6 promoter region and lung cancer risk: a meta-analysis
Tumor Biology (2014)
-
A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk
Journal of Cancer Research and Clinical Oncology (2013)
-
PDGFRa mutations in humans with isolated cleft palate
European Journal of Human Genetics (2012)
-
Mannose-binding lectin haplotypes influence Brucella abortus infection in the water buffalo (Bubalus bubalis)
Immunogenetics (2008)