SYNCYTIN-1 as a new marker for pre-eclampsia, the second leading cause of death in pregnant women

• Faculty of Medicine, Comenius University in Bratislava
• Institute of Medical biology, Genetics and Clinical Genetics FM CU in Bratislava
• Institute of Pathological Anatomy FM CU in Bratislava
• 1st Department of Gynaecology and Obstetrics FM CU in Bratislava, St. Cyril and Method's Hospital in Bratislava
• 2nd Department of Gynaecology and Obstetrics FM CU in Bratislava, Ružinov Hospital in Bratislava

Preeclampsia as a disease

Preeclampsia (PE) is a multisystem disorder, that affects approximately 5 % of pregnancies worldwide. PE is one of the leading causes of maternal, fetal and neonatal morbidity or mortality. The onset of PE occurs about 20. gestational week (exceptionally before 20 weeks; Tanaka et al., 2015) and it is characterized by many heterogenous symptoms. The most detectable symptoms are hypertension and proteinuria, which also serves as the main diagnostic markers. In addition, several other symptoms could be linked to PE such as abnormalities of placenta, kidney, and liver, neurological and hematological complications which could lead to fetal damage. In general, the treatment of PE is to manage the symptoms however the disorder persists. Since PE is a disorder of the placenta, the only direct treatment is the delivery. More than half of women are forced to undergo the delivery in the form of a section (Roberts and Lain, 2002; Zhang et al, 2003; Wagner, 2004; Liu et al., 2009).

Diagnostic criteria

The major criteria for diagnosing the disease are de novo hypertension, which appears after 20 weeks gestation, in combination with proteinuria. Preeclamptic hypertension is defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg, measured twice, at intervals of 4 – 6 hours. Proteinuria (elevated levels of proteins in urine) is determined by the protein content in urine ≥ 300 mg/day (Mol et al., 2016; Townsend et al., 2016).

There is a group of abnormalities, known together as the hypertensive disorders of pregnancy, which includes preeclampsia and gestational hypertension. It is possible, that hypertension is elevated for the first time after 20 weeks gestation, suggesting a potential onset of PE, but the patient does not suffer from proteinuria. This condition is classified as having gestational hypertension. One of four women, suffering from gestational hypertension, subsequently develop proteinuria, leading to the onset of PE (Saudan et al., 1998; Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy, 2000; Wagner, 2004). The similarity of symptoms detected in the hypertensive disorders of are the reason of the unclear and inaccurate diagnostics of PE.

Dong et al. monitored PE in women of varying severity of proteinuria. Based on the obtained data, authors suggest that the level of proteins in urine may be associated with the development of severity of PE. In addition, they refer, that the amount of proteinuria is positively correlated with time of onset in PE, but time between the onset of PE and delivery is not associated with the severity of proteinuria (Dong et al., 2017). Despite the mentioned diagnostic features, up to 10 % of patients with PE have no proteinuria at the time of clinical presentation (Sibai, 1990; Thornton et al., 2010; Dong et al., 2017). These knowledges complicate the detection of disorder onset causing difficulties in diagnostics of PE.

Trophoblast and placenta

The structure and functionality of the placenta is related to the health of mother and developing fetus (Guttmacher et al., 2014). The process of placentation is the key point in PE, because the placenta formation provides the functional connection between mother and fetus. The result of placentation is the implantation of blastocyst in uterus. Invasion of the trophoblast into the maternal endometrium is necessary for placentation. The blastocyst contains a layer of cytotrophoblast cells on its surface, the cells that fuse and form a multinucleated syncytiotrophoblast (fig. 1). Only the multinucleated unit can invade into the maternal endometrium, what is indispensable for the proper placentation process (Popek, 1999; Ji et al., 2013).

Syncytin-1 in placentation

Syncytin-1 protein is encoded by ERVW-1 gene belonging to the human endogenous retroviral family – HERV-W. The highest level of ERVW-1 expression was detected in placenta. The product of this gene mediates the cytotrophoblast cell fusion, from which differentiates multinucleated syncytiotrophoblast (fig. 2). Without the fusogenic activity of syncytin-1, normal placentation could not occur (Blond et al., 1999; Blond et al., 2000; Mi et al., 2000; Voisset et al, 2000; Huang et al., 2014).

Molecular structure of ERVW-1 gene

ERVW-1 gene is located on q21.2 of chromosome 7 in the genome. It consists of three, originally retroviral, parts of which gag and pol regions are found in the human genome as pseudogenes, while the env (coding envelope protein) region has been functionally preserved. Only the env region has retained complete retroviral ORF (Open Reading Frame), whose product is fusogenic protein syncytin-1, required for the cell fusion in syncytiotrophoblast forming (fig. 3). Env sequence is flanked by two LTR (Long Terminal Repeat) regions. Downstream from 5ʼLTR is laying an intron with the size of 2 kb (Blond et al, 1999; Blond et al., 2000; Voisset et al., 2000).

The structure of the syncytin-1 protein

The functional syncytin-1 consist of surface-associated unit (SU) and transmembrane unit (TM), which are linked to each other by disulfide bonds. SU plays a role in interaction with receptors. The role of the TM is to cross the membrane and anchor the peptide in the cell membrane. Moreover, TM contains the potential immunosuppressive domain, which has a competence to supress the immune response of mother towards fetus. Fully functional syncytin-1 is organised as a homotrimeric structure. Without this spatial arrangement, it loses the fusogenic activity (Fass and Kim, 1995; Cheynet et al., 2005).

Syncytin-1 and preeclampsia

According to Holder et al., the level of syncytin-1 is elevated in placenta of PE women, compared to physiological placentas (Holder et al., 2012). This founding contrasts with other studies, they refer decreased expression of syncytin-1 at the mRNA but also protein level (Lee et al., 2001; Knerr et al., 2002; Vargas et al., 2011). In addition, many studies included inadequate number of samples considering the frequency of incidence of PE. Despite the knowledge obtained regarding the association between syncytin-1 and PE, the overall conclusions are still unclear. Consequently, there is a need for a closer study of the pathophysiology of PE in terms of correlation of ERVW-1 gene expression with the disease, and the results need to be demonstrated in a sufficiently large sample of patients.

References

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