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

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

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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.

Original languageEnglish
Article number141
Number of pages23
JournalBmc Medicine
Volume20
DOIs
Publication statusPublished - Apr 2022
Publication typeA1 Journal article-refereed

Keywords

  • Alpha-1-antitrypsin
  • Placenta
  • Preterm birth
  • Proteomics
  • SERPINA1
  • Trophoblast
  • Whole exome sequencing

Publication forum classification

  • Publication forum level 2

ASJC Scopus subject areas

  • Medicine(all)

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