Relation Between HLA-G Gene Null Allele (HLA-G*0105N) and Recurrent Miscarriage

Abstract

: Human leukocyte antigen-G (HLA-G) is a nonclassical HLA-class I antigen located on chromosome 6. HLA-G is highly expressed on cytotrophoblast cells at the fetomaternal interface and involved in the development of pregnant uterus as an immune privileged site. Expression of HLA-G is thought to have a critical role in the protection of the semiallogenic fetus from maternal immune attack during pregnancy. HLA-G molecules bind inhibitory receptors on maternal T cells and NK cells and subsequently inhibit their cytolytic activities. Because of mRNA alternative splicing of HLA-G primary transcript, the HLA-G protein exists in both membrane-bound (HLA-G1 to G4) and soluble (HLA-G5 to G7) isoforms. HLA-G gene contains 15 alleles, including the HLA-G*0105N null allele. A single base-pair deletion of a cytosine (1597delC) results in open reading frame mutation, which leads to a premature stop codon. The HLA-G*0105N allele is unable to generate the HLA-G1, HLA-G5, and HLA-G4 isoforms. However, it is still able to produce other HLA-G proteins, in which exon 3 is removed by alternative splicing, including HLA-G2, G3, G6 and G7 isoforms. HLA-G*0105N null allele has been described in healthy adults with successful and normal pregnancies, which suggests that HLA-G function is not restricted to the HLA-G1 isoform. Description of healthy individual homozygous for HLA-G*0105N allele recommends that truncated HLA-G2 and G3 isoforms encoded by null allele are able to compensate for the lack of the HLA-G1, G4 and G5 isoforms. Results of the numerous studies on the null allele of HLA-G gene indicated that its selection may have increased the frequency of the HLA-G*0105N. Studies on the null allele of HLA-G gene could be useful in determining the frequency of genetic variants of HLA-G alleles in different ethnic groups.