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Promoter haplotype combinations of the platelet-derived growth factor α-receptor gene predispose to human neural tube defects

Nature Genetics volume 27, pages 215–217 (2001)Cite this article

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.

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Figure 1: Promoter haplotypes resulting from polymorphisms in the −1,589/+118 nucleotide sequence of PDGFRA (ref. 7).
Figure 2: Distribution of the different PDGFRA promoter haplotypes in a group of 49 familial spina bifida patients, 76 sporadic spina bifida patients and 77 control individuals.
Figure 3: Distribution of promoter activity of transfected 5′ PDGFRA haplotypes in U2-OS cells.

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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.

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Authors and Affiliations

  1. Department of Cell Biology, University of Nijmegen, Nijmegen, The Netherlands

    Paul H.L.J. Joosten, Mascha Toepoel & Everardus J.J. Van Zoelen

  2. Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands

    Edwin C.M. Mariman

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  1. Paul H.L.J. Joosten
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Correspondence to Paul H.L.J. Joosten.

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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

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