Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family

Nature Genetics volume 37, pages 514–519 (2005)Cite this article

Abstract

Preeclampsia is a pregnancy-associated disease with maternal symptoms but placental origin. Epigenetic inheritance is involved in some populations. By sequence analysis of 17 genes in the 10q22 region with maternal effects, we narrowed the minimal critical region linked with preeclampsia in the Netherlands to 444 kb. All but one gene in this region, which lies within a female-specific recombination hotspot, encode DNA- or RNA-binding proteins. One gene, STOX1 (also called C10orf24), contained five different missense mutations, identical between affected sisters, cosegregating with the preeclamptic phenotype and following matrilineal inheritance. Four STOX1 transcripts are expressed in early placenta, including invasive extravillus trophoblast, generating three different isoforms. All contain a winged helix domain related to the forkhead (FOX) family. The largest STOX1 isoform has exclusive nuclear or cytoplasmic expression, indicating activation and inactivation, respectively, of the PI3K-Akt-FOX pathway. Because all 38 FOX proteins and all 8 STOX1 homologs have either tyrosine or phenylalanine at position 153, the predominant Y153H variation is highly mutagenic by conservation criteria but subject to incomplete penetrance. STOX1 is a candidate for preeclampsia controlling polyploidization of extravillus trophoblast.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Minimal critical region on 10q22 with maximal sharing of both alleles in affected sisters with preeclampsia.
Figure 2: Features of genes in the minimal critical region of preeclampsia (RUFY2–CCAR1).
Figure 3: Transcriptional organization and expression pattern of STOX1 in early placenta.
Figure 4: Matrilineal transmission of heterozygous missense mutations in preeclampsia.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Arngrimsson, R. et al. A genome-wide scan reveals a maternal susceptibility locus for preeclampsia on chromosome 2p13. Hum. Mol. Gen. 8, 1799–1805 (1999).

    Article  CAS  Google Scholar 

  2. Laivuori, H. et al. Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families. Am. J. Hum. Genet. 72, 168–177 (2003).

    Article  CAS  Google Scholar 

  3. Lachmeijer, A.M. et al. A genome-wide scan for preeclampsia in the Netherlands. Eur. J. Hum. Gen. 9, 758–764 (2001).

    Article  CAS  Google Scholar 

  4. Oudejans, C.B.M. et al. The parent-of-origin effect of 10q22 in preeclamptic females coincides with two regions clustered for genes with downregulated expression in androgenetic placentas. Mol. Hum. Reprod. 10, 589–598 (2004).

    Article  CAS  Google Scholar 

  5. Kanayama, N. et al. Deficiency in p57kip2 expression induces preeclampsia-like symptoms in mice. Mol. Hum. Reprod. 8, 1129–1135 (2002).

    Article  CAS  Google Scholar 

  6. Van Dijk, M. et al. Differential downregulation of αT-catenin expression in placenta: trophoblast cell type-dependent imprinting of the CTNNA3 gene. Gene Expr. Patterns 5, 61–65 (2004).

    Article  CAS  Google Scholar 

  7. Valdez, B.C., Yang, H., Hong, E. & Sequitin, A.M. Genomic structure of newly identified paralogue of RNA helicase II/Gu: detection of pseudogenes and multiple alternatively spliced mRNAs. Gene 284, 53–61 (2002).

    Article  CAS  Google Scholar 

  8. Deloukas, P. et al. The DNA sequence and comparative analysis of human chromosome 10. Nature 429, 375–381 (2004).

    Article  CAS  Google Scholar 

  9. Paldi, A., Gyapay, G. & Jami, J. Imprinted chromosomal regions of the human genome display sex-specific meiotic recombination frequencies. Curr. Biol. 5, 1030–1035 (1995).

    Article  CAS  Google Scholar 

  10. Ng, C. & Henikoff, S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 12, 436–446 (2002).

    Article  CAS  Google Scholar 

  11. Guenther, C. & Gariga, G. Asymmetric distribution of the C. elegans HAM-1 protein in neuroblasts enables daughter cells to adopt distinct fates. Development 122, 3509–3518 (1996).

    CAS  PubMed  Google Scholar 

  12. Nagase, T., Kikuno, R., Ishikawa, K.I., Hirosawa, M. & Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7, 65–73 (2000).

    Article  CAS  Google Scholar 

  13. Stevens, K., Cirillo, L. & Zaret, K.S. Creating temperature-sensitive winged helix transcription factors. J. Biol. Chem. 275, 30471–30477 (2000).

    Article  CAS  Google Scholar 

  14. Obsil, T., Ghirlando, R., Anderson, D.E., Burgess Hickman, A. & Dyda, F. Two 14-3-3 binding motifs are required for stable association of forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Biochemistry 42, 15264–15272 (2003).

    Article  CAS  Google Scholar 

  15. Zhao, X. et al. Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent- and -independent mechanisms. Biochem. J. 378, 839–849 (2004).

    Article  CAS  Google Scholar 

  16. Matsuzaki, H., Daitoku, H., Hatta, M., Tanaka, K. & Fukamizu, A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc. Natl. Acad. Sci. USA 100, 11285–11290 (2003).

    Article  CAS  Google Scholar 

  17. Nishimura, D.Y. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat. Genet. 19, 140–147 (1998).

    Article  CAS  Google Scholar 

  18. Kamei, T. et al. The phosphatidylinositol 3-kinase/Akt signaling pathway modulates the endocrine differentiation of trophoblast cells. Mol. Endocrin. 16, 1469–1481 (2002).

    Article  CAS  Google Scholar 

  19. Hattori, N., Davies, T.C., Anson-Cartwright, L. & Cross, J.C. Periodic expression of the cyclin-dependent kinase inhibitor p57(Kip2) in trophoblast giant cells defines a G2-like gap phase of the endocycle. Mol. Biol. Cell 11, 1073–1045 (2000).

    Article  Google Scholar 

  20. Guidotti, J.E. et al. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J. Biol. Chem. 278, 19095–19101 (2003).

    Article  CAS  Google Scholar 

  21. Harrison, G.A. et al. A genomewide linkage study of preeclampsia/eclampsia reveals evidence for a candidate region on 4q. Am. J. Hum. Genet. 60, 1158–1167 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Leegwater, P.A.J. et al. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat. Genet. 29, 383–388 (2001).

    Article  CAS  Google Scholar 

  23. van Steensel, B., Delrow, J. & Henikoff, S. Chromatin profiling using targeted DNA adenine methyltransferase. Nat. Genet. 27, 304–308 (2001).

    Article  CAS  Google Scholar 

  24. Go, A.T. et al. Detection of placental transcription factor mRNA in maternal plasma. Clin. Chem. 50, 1413–1414 (2004).

    Article  CAS  Google Scholar 

  25. Poon, L.L., Leung, T.N., Lau, T.K., Chow, K.C. & Lo, Y.M. Differential DNA methylation between fetus and mother as a strategy for detecting fetal DNA in maternal plasma. Clin. Chem. 48, 35–41 (2002).

    CAS  PubMed  Google Scholar 

  26. Riyazi, N. et al. Low-molecular-weight heparin combined with aspirin in pregnant women with trombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur. J. Obstet. Gyn. Reprod. Biol. 80, 49–54 (1998).

    Article  CAS  Google Scholar 

  27. Quenby, S., Mountfeld, S., Cartwright, J.E., Whitley, G.S. & Vince, G. Effects of low-molecular-weight and unfractionated heparin on trophoblast function. Obstet. Gynecol. 104, 354–361 (2004).

    Article  CAS  Google Scholar 

  28. Mello, G. et al. Low-molecular weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women. Hypertension 45, 1–6 (2005).

    Article  Google Scholar 

  29. Saleem, R.A., Banerjee-Basu, S., Berry, F.B., Baxevanis, A.D. & Walter, M.A. Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1. Am. J. Hum. Genet. 68, 627–641 (2001).

    Article  CAS  Google Scholar 

  30. Lewis, A. et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat. Genet. 36, 1291–1295 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the affected individuals, their relatives and their doctors for their support; J. Cartwright for providing SGHPL5 cells; and H. Kato for providing molar pregnancy samples. This work is supported by an Earmarked grant from the Foundation for Clinical Chemistry.

Author information

Authors and Affiliations

  1. Department of Clinical Chemistry, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands

    Marie van Dijk, Joyce Mulders, Ankie Poutsma, Andrea A M Könst, Marinus A Blankenstein & Cees B M Oudejans

  2. Department of Clinical Genetics and Human Genetics, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands

    Augusta M A Lachmeijer

  3. Department of Obstetrics/Gynaecology, Adelaide University, Adelaide, Australia

    Gustaaf A Dekker

Authors
  1. Marie van Dijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joyce Mulders
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ankie Poutsma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea A M Könst
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Augusta M A Lachmeijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gustaaf A Dekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marinus A Blankenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cees B M Oudejans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cees B M Oudejans.

Ethics declarations

Competing interests

The VU University Medical Center has filed a patent application related to a method for diagnosing preeclampsia.

Supplementary information

Supplementary Table 1

Alignment of FOX proteins with the C10orf24 protein and its homologs. (PDF 1571 kb)

Supplementary Table 2

Missense and nonsense mutations in C10orf24 shared between preeclamptic sisters. (PDF 64 kb)

Supplementary Table 3

Primer and PCR characteristics used for coding sequence analysis of 17 genes in the 10q22 region of preeclamptic females. (PDF 41 kb)

Supplementary Table 4

Primer and PCR characteristics used for transcript analysis and cloning of C10orf24. (PDF 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Dijk, M., Mulders, J., Poutsma, A. et al. Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family. Nat Genet 37, 514–519 (2005). https://doi.org/10.1038/ng1541

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1541

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing