Preeclampsia is a pregnancy-associated disease with maternal outcome but placental origin. Genome wide linkage analysis revealed that preeclampsia segregates with at least four different susceptibility loci: 2p12 (Iceland), 2p25 (Finland), 9p13 (Finland) and 10q22 (the Netherlands). The Dutch locus is subject to a parent-of-origin effect. By sequence analysis of 17 genes within the 10q22 region with maternal effect, one gene was identified, STOX1, containing five 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, coding for three different isoforms. All contain a winged helix domain related to the forkhead (FOX) family. Only one paralog is known on 4q35 in a region linked with preeclampsia in Australia. The largest STOX1 isoform shows exclusive nuclear or cytoplasmic expression indicating activation and inactivation, respectively, of the PI3K-Akt-FOX pathway. Because all 38 FOX proteins and 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 gene for preeclampsia controlling polyploidization of extravillus trophoblast. Founder dependent mutations in paralogous genes similar to STOX1 or sharing the same pathway, but located on different chromosomes, could underlie preeclampsia in other populations than the Dutch.
|Translated title of the contribution||Epigenetics of preeclampsia|
|Number of pages||5|
|Journal||Reproduction Humaine et Hormones|
|Publication status||Published - Jun 2008|