Preeclampsia/eclampsia 4

A number sign (#) is used with this entry because of evidence that preeclampsia/eclampsia-4 can be caused by heterozygous mutation in the STOX1 gene (609397) on chromosome 10q22.

For a phenotypic description and a discussion of genetic heterogeneity of preeclampsia/eclampsia, see PEE1 (189800).

Lachmeijer et al. (2001) performed a genome scan using 293 polymorphic markers in 67 Dutch sib-pair families affected by preeclampsia, eclampsia, or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). Analysis in 38 preeclampsia families showed suggestive evidence for linkage on chromosome 22q at 32.4 cM (lod score of 2.41) and on chromosome 10q at 93.9 cM (lod score of 2.38).

By affected sib-pair linkage analysis of 24 families with preeclampsia, Oudejans et al. (2004) confirmed a susceptibility locus on chromosome 10q22.1 in Dutch females, obtaining a multipoint nonparametric linkage score of 3.6 near marker D10S1432. Haplotype analysis showed a parent-of-origin effect with maximal allele sharing in the affected sibs for maternally derived alleles in all families, suggesting the presence of maternally expressed imprinted genes. Using RT-PCR, the placental expression of 55 genes in the 10q22 region with imprinting-related features was compared to expression in androgenetic (molar) pregnancies of identical gestational age. Two regions on 10q22 were identified, each containing 5 genes with downregulated expression in androgenetic placentas and each coinciding with the regions with maximal allele sharing in the preeclamptic sisters. Oudejans et al. (2004) concluded that preeclampsia involves maternally expressed imprinted genes that operate in the first trimester.

In preeclamptic sib pairs from the 24 Dutch families previously described by Oudejans et al. (2004), van Dijk et al. (2005) sequenced 17 genes in the 10q22 region with maternal effects and narrowed the minimal critical region to 444 kb within a female-specific recombination hotspot. The authors identified 5 different missense mutations in the STOX1 gene, including Y153H (609397.0001) and E608D (609397.0002); all 5 mutations were identical between affected sisters, cosegregated with the preeclamptic phenotype, and followed matrilineal inheritance. The authors traced informative nucleotide variations across 3 generations in 6 of the 24 families and found that the mutation on the maternal allele in the second generation was transmitted to 13 children in the third generation who were born from preeclamptic pregnancies, whereas the 2 children who were born of normal pregnancies did not carry the mutated maternal allele. There was one exception in the mother-child transmission of the Y153H allele: the mother's first pregnancy was preeclamptic and the second normal but both of her children carried her mutated allele. The authors noted that during the mother's second pregnancy, she had participated in a prospective preventive trial of subcutaneous low molecular weight heparin. Van Dijk et al. (2005) concluded that STOX1 is a maternal-effect gene and that loss of function of STOX1 in the placenta underlies preeclampsia in Dutch females.

Kivinen et al. (2007) failed to find evidence in support of STOX1 as a preeclampsia gene in a cohort of 245 Finnish women with preeclampsia using genetic linkage analysis and haplotype analysis. They noted that STOX1 expression studies with RNA from placentas of 8 preeclamptic and 6 uncomplicated deliveries failed to show a significant difference in expression levels.