The expression and functional activity of membrane-bound human leukocyte antigen-G1 are influenced by the 3′-untranslated region

Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

“…14 Contrary to the − 1140 A4T SNV, the functionality of this indel is well established, with a significant effect on the HLA-G mRNA stability, the magnitude of HLA-G production and the level of inhibition of natural killer cell cytotoxicity. [56][57][58][59][60][61] Therefore, a high LD between this indel and the − 1140 A4T promoter variant may explain the pattern observed at the − 1140 position. A significant allelic association between these two variants was indeed observed using the 1KG data, with moderate-to-strong LD depending on the population analyzed (r 2 values ranging from 0.57-0.62 in Africa and America to 0.88-0.92 in Europe and East Asia) (A Sabbagh, unpublished data).…”

HLA-G as a Tolerogenic Molecule in Transplantation and Pregnancy

“…Furthermore, there is the possibility of linkage disequilibrium (LD) among polymorphic sites in the 3′UTR with polymorphic sites in the 5′URR may leading to a different posttranscriptional patterns and changes in the HLA-G expression [128, 137, 138]. Importantly, mRNA from 14 bp insertion shows an increased surface expression of HLA-G1 expression relative to mRNA lacking the 14 bp sequence but the ratio of release sHLA-G1 to surface expressed HLA-G1 is lower [139]. In line with this, low sHLA-G levels are often associated with the 14 bp insertion genotype (+14/+14 bp) in women having experienced pregnancy complications [140–143].…”

Controlling the Immunological Crosstalk during Conception and Pregnancy: HLA-G in Reproduction

“…Since the 3′UTR of the HLA-G gene exhibits several regulatory elements including AU-rich motifs, a poly-A signal, as well as signals that regulate the spatial and temporal expression of mRNA, the polymorphic sites may influence mRNA stability, turnover, mobility, and splicing pattern (20, 28, 30). A 14-bp ins/del (rs66554220) located in exon 8 is the best studied polymorphism in the 3′UTR, and has been shown to influence HLA-G mRNA transcript size and stability (19, 28, 30, 31, 40–42). The presence of the 14-bp-insertion sequence introduces an alternative splice site that generates a 92-bp deletion in the 3′UTR of the HLA-G mRNAs, and this alternative splice form seems to have an impact on the expression levels of HLA-G (5, 28, 40, 41).…”

“…Experiments with HLA-G transductants showed that K562 cells with the 3′UTR 14 bp-insertion sequence had more stable mRNA compared to transductants lacking the 14-bp insertion. The study also looked at the functional impact of the 14-bp insertion on NK cell cytotoxicity, and found that K562 transductant cells carrying the 14-bp-insertion sequence were significantly less sensitive to NK cell cytotoxicity as compared to K562 cells that did not carry the 14-bp-insertion sequence (42). However, this study only investigated the isolated role of the 14-bp sequence in experiments performed with the use of a cell line, and the importance of the 14-bp-insertion sequence may be modulated or influenced by other linked polymorphisms in the 3′UTR, and in future studies it is important to study different HLA-G haplotypes.…”