The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas

Abstract

By affected sib-pair linkage analysis of 24 families with pre-eclampsia, we confirm a susceptibility locus on chromosome 10q22.1 in Dutch females: a multipoint non-parametric linkage score of 3.6 near marker D10S1432 was obtained. Haplotype analysis showed a parent-of-origin effect: maximal allele sharing in the affected sibs was found for maternally derived alleles in all families, but not for the paternally derived alleles. As matrilineal inheritance suggests the presence of maternally expressed imprinted genes, while imprinting operates predominantly in (extra)embryonic tissues, all genes (n=132) known on 10q22 between GATA121A08 and D10S580 were screened for seven sequence-related features associated with imprinting and subsequently tested for expression in first trimester placenta. Placental expression of genes selected in this way (n=55) was compared with expression in androgenetic placentas of identical gestational age. Two regions on 10q22 were identified with developmentally co-repressed genes with non-random chromosomal distribution. Interestingly, these two clusters, near CTNNA3 and KCNMA1 and each containing five genes with down-regulated expression in androgenetic placentas, coincided with the regions with maximal maternal allele sharing seen in the pre-eclamptic sisters. Our linkage and expression data are compatible with the concept that pre-eclampsia involves maternally expressed imprinted genes that operate in the first trimester placenta.

Familial aggregation of preeclampsia and intrauterine growth restriction in a genetically isolated population in The Netherlands

“…13 However, our observations are at odds with prior findings of a maternal parent-of-origin effect in Dutch preeclampsia patients. 8 Differences between the study of Oudejans et al 8 and our study may be explained by the selection of patients. Oudejans et al 8 included affected sib pairs of whom a majority were born to mothers who experienced preeclampsia-or pregnancy-induced hypertension.…”

“…Oudejans et al 8 included affected sib pairs of whom a majority were born to mothers who experienced preeclampsia-or pregnancy-induced hypertension. 8 In this way, they aimed to target a familial form of preeclampsia with early onset disease. This highly selected group represents only a small proportion of the overall group of preeclamptic women.…”

“…Most of the previous studies on familial aggregation and parent-of-origin effects are based on two or three generations. 5,7,8,29 The availability of the genealogy revealed familial aggregation in seemingly unrelated cases. The extended pedigree containing a large proportion of the women with previous preeclampsia and IUGR may prove to be helpful in future in discovering genes involved in the pathogenesis of both disorders.…”

“…8,9 Imprinted genes play a fundamental role in the regulation of human growth and disruption of these genes may cause growth disturbances as is seen in uniparental disomies. 9 Recently, dysregulation of imprinted genes was reported in human placental tissue of IUGR pregnancies.…”

Maternal Nodal inversely affects NODAL and STOX1 expression in the fetal placenta

“…The chromosomal location of NODAL is in the same linkage area as the placental (fetal) PE susceptibility gene STOX1, which is associated with the familial form of early-onset, IUGR-complicated PE (van Dijk et al, 2005). The PE susceptibility linkage locus originally identified on chromosome 10q22 by microsatellite marker analysis showed matrilineal inheritance (Oudejans et al, 2004). Investigating the individual genes on this locus for imprinting features revealed NODAL as one of the genes with reduced expression in the androgenetic placenta, suggestive of imprinting.…”