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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Premature Birth | Research article

Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth

Authors: Heli Tiensuu, Antti M. Haapalainen, Pinja Tissarinen, Anu Pasanen, Tomi A. Määttä, Johanna M. Huusko, Steffen Ohlmeier, Ulrich Bergmann, Marja Ojaniemi, Louis J. Muglia, Mikko Hallman, Mika Rämet

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth.

Methods

We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas.

Results

Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit–Robo signaling, and extracellular matrix organization.

Conclusions

Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.

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Metadata
Title
Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth
Authors
Heli Tiensuu
Antti M. Haapalainen
Pinja Tissarinen
Anu Pasanen
Tomi A. Määttä
Johanna M. Huusko
Steffen Ohlmeier
Ulrich Bergmann
Marja Ojaniemi
Louis J. Muglia
Mikko Hallman
Mika Rämet
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Premature Birth
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02339-8

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