Allelic imbalance modulates surface expression of the tolerance-inducing HLA-G molecule on primary trophoblast cells.
The HLA-G molecule is expressed on trophoblast cells at the feto-maternal interface, where it interacts with local immune cells, and upholds tolerance against the semi-allogeneic fetus. Aberrant HLA-G expression in the placenta and reduced soluble HLA-G levels are observed in pregnancy complications, partly explained by HLA-G polymorphisms which are associated with differences in the alternative splicing pattern and of the stability of HLA-G mRNA. Of special importance is a 14 bp insertion/deletion polymorphism located in the 3'-untranslated region of the HLA-G gene. In the current study, we present novel evidence for allelic imbalance of the 14 bp insertion/deletion polymorphism, using a very accurate and sensitive Digital droplet PCR technique. Allelic imbalance in heterozygous samples was observed as differential expression levels of 14 bp insertion/deletion allele-specific mRNA transcripts, which was further associated with low levels of HLA-G surface expression on primary trophoblast cells. Full gene sequencing of HLA-G allowed us to study correlations between HLA-G extended haplotypes and single-nucleotide polymorphisms and HLA-G surface expression. We found that a 1:1 expression (allelic balance) of the 14 bp insertion/deletion mRNA alleles was associated with high surface expression of HLA-G and with a specific HLA-G extended haplotype. The 14 bp del/del genotype was associated with a significantly lower abundance of the G1 mRNA isoform, and a higher abundance of the G3 mRNA isoform. Overall, the present study provides original evidence for allelic imbalance of the 14 bp insertion/deletion polymorphism, which influences HLA-G surface expression on primary trophoblast cells, considered to be important in the pathogenesis of pre-eclampsia and other pregnancy complications.
['Djurisic|S|S|', 'Teiblum|S|S|', 'Tolstrup|C K|CK|', 'Christiansen|O B|OB|', 'Hviid|T V F|TV|']
D020413:3' Untranslated Regions D000029:Abortion, Legal D000483:Alleles D022981:Allelic Imbalance D017398:Alternative Splicing D001483:Base Sequence D005260:Female D059951:HLA-G Antigens D006239:Haplotypes D006579:Heterozygote D006801:Humans D054643:INDEL Mutation D007108:Immune Tolerance D008969:Molecular Sequence Data D016133:Polymerase Chain Reaction D011110:Polymorphism, Genetic D011247:Pregnancy D011261:Pregnancy Trimester, First D061251:Primary Cell Culture D017422:Sequence Analysis, DNA D014327:Trophoblasts
allelic imbalance HLA-G pregnancy polymorphism 3′ untranslated region