A molecular genetic study investigating the role of maternal and placental laeverin gene mutation and fetal whole genome copy number variations in the pathophysiology of preeclampsia

Abstract

Summary Preeclampsia is a clinical syndrome affecting only pregnant women and is defined as new onset of hypertension and proteinuria after 20 weeks of gestation. Approximately, 2-7 % of all pregnant women in the developed world are affected by this condition and it is a major cause of maternal and fetal morbidity and mortality. Despite intensive research the pathophysiology of preeclampsia is not fully understood. Laeverin is a gene encoding for a membrane bound-cell surface metallopeptidase (MMP) expressed on extravillous trophoblast (EVT). The EVT cells are responsible for remodelling of maternal spiral arteries during placental development. It has been suggested that laeverin may be involved in the regulation of invasive EVTs during early human placentation. Gene expression studies using microarrays have documented that laeverin is ten fold-up regulated in preeclamptic placentas compared to normal placentas, indicating its possible involvement in the pathophysiology of preeclampsia. Immune fluorescence studies of placental tissue sections from normal and preeclamptic patients documented that in preeclamptic placentas laeverin is expressed in cytoplasma, while in normal placentas it is expressed in the cell membrane. The laeverin gene was therefore sequenced to detect possible mutations which could be linked to the pathogenesis of preeclampsia. We found one variant documented exclusively in blood from one preeclamptic patient in exon 7 position g.1459G˃A which replaces one Glutamic acid with Lysine. Since it was not present in any normal controls this may be a pathogenic mutation and should be further investigated. Several studies have indicated a possible fetal contribution to development of preeclampsia. By performing array comparative genomic hybridization (aCGH) analysis which detects deletions and duplications in the whole genome in one single test, we investigated if umbilical cord blood from fetuses of preeclamptic women contained mutations which may be associated with preeclampsia. These results were compared to the results from an aCGH analysis on maternal blood. Numerous copy number variations were detected and some of them contained genes involved in vesicle transportation within the Golgi apparatus, protein folding, protein trafficking, immunological processes, maintenance of cell membranes, pregnancy-specific glycoproteins, complement system, tissue invasion and angiogenesis. These genes should be further investigated to examine their potential role in the pathophysiology of preeclampsia.