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

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.

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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.

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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

Correspondence to Cees B M Oudejans.

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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)

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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

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