Alternative titles; symbols
HGNC Approved Gene Symbol: HLA-G
Cytogenetic location: 6p22.1 Genomic coordinates (GRCh38): 6:29,826,474-29,831,021 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.1 | {Asthma, susceptibility to} | 600807 | Autosomal dominant | 2 |
TCA, a locus about 10 cM telomeric to HLA-A (142800) on 6p, codes for class I antigens in the surface of T lymphocytes (Van Leeuwen, 1982). It is a beta-2-microglobulin-related, class I antigen.
Geraghty et al. (1987) cloned and sequenced an HLA class I gene, HLA-6.0. This gene is very similar to the HLA-A, -B (142830), and -C (142840) genes, but the protein encoded by HLA-6.0 differs from the products of the other 3 genes in that it lacks most of the intracellular segment. This suggested that it is the structural homolog of a murine Qa region class I gene (Rodriguez de Cordoba et al., 1985).
Extravillous trophoblasts from normal human placenta and the BeWo adherent human choriocarcinoma cell line express an unusual form of class I HLA molecule. This molecule has an H chain of approximately 40 kD and is apparently nonpolymorphic. Ellis et al. (1990) isolated and sequenced a cDNA clone for this class I HLA antigen. The nucleotide sequence showed a high degree of homology with the published sequence of a genomic clone, HLA 6.0. The new locus was provisionally designated HLAG. Using PCR, Ellis et al. (1990) demonstrated similar HLA class I sequences in cDNA from normal extravillous trophoblasts. Although there was some nucleotide sequence polymorphism, the amino acid sequence of the molecule was conserved; hence, it is unlikely to provoke immune responses even though it is found at the fetal-maternal interface.
The HLA-G gene is monomorphic and the only MHC antigen expressed on cytotrophoblast cells of placenta. By using PCR amplification with HLA-G primers specific for exon 3, Kirszenbaum et al. (1994) demonstrated an alternatively spliced form of HLA-G mRNA present in fetal first-trimester trophoblasts and lacking exon 4. They commented that this low abundance transcript may encode the protein that excludes the alpha-3 domain and by conformational changes may present a different ability to bind to peptides. Moreover, expression of the HLA-G transcript was found in adult peripheral lymphocytes and equally in B- and T-cell populations. By Northern blot and RT-PCR assays using an HLA-G locus-specific probe and primers, Onno et al. (1994) found that the gene is transcribed in a variety of cells and adult tissues as well as fetal tissues. In most tissues, the mRNA level was orders of magnitude lower than the level of classic class I genes in the same tissues. Alternative splicing of the HLA-G primary transcript was different from tissue to tissue and may be regulated in a tissue-specific fashion.
By pulsed field gel electrophoresis, Schmidt and Orr (1991) determined that HLA-G is closer to HLA-A (142800) than is HLA-F (143110) on chromosome 6p21. A maximum distance of 490 kb was found between HLA-A and HLA-F. In the study of YAC clones from the class I region of the MHC, Geraghty et al. (1992) detected a highly polymorphic region between the HLA-A and HLA-G genes. This region was deleted in certain HLA haplotypes, shortening the distance between the 2 genes by more than 50 kb. Morales et al. (1993) described 3 new HLA-G alleles and demonstrated linkage disequilibrium with HLA-A.
Onno et al. (1994) suggested a new hypothesis for HLA-G function: HLA protein synthesis may be induced under stressful conditions such as infection or transformation, and this may provide a mechanism to target damage in somatic cells for immune elimination.
Generally, transplants between 2 different, MHC-mismatched inbred strains are rejected, whereas MHC-matched transplants are accepted. An F1 hybrid offspring produced by mating of 2 inbred strains codominantly expresses MHC alleles from both parents. The F1 hybrid is capable of accepting a transplant from either parent, but each parent rejects F1 hybrid tissue (because it has 'foreign' MHC molecules from the other parent). These clear cut laws guide clinical transplantation of solid organs in human patients. One obvious violation of the classic transplantation paradigms is the case of a mother's successful ability to nurture a fetus in the womb. Yokoyama (1997) reviewed evidence that maternal-fetal tolerance is due to a specific and direct interaction (or lack thereof) between fetal and maternal cells. Rouas-Freiss et al. (1997) provided evidence involving HLA-G and natural killer (NK) cells in maternal-fetal tolerance.
Considering the well-established role of nonclassic HLA-G class I molecules in inhibiting natural killer cell function, the consequence of abnormal HLA-G expression in malignant cells should be the escape of tumors from immunosurveillance. To examine this hypothesis, Paul et al. (1998) analyzed HLA-G expression and NK sensitivity in human malignant melanoma cells. Two melanoma cell lines exhibited a high level of HLA-G transcription with differential HLA-G isoform transcription and protein expression patterns. A higher level of HLA-G transcription ex vivo was detected in a skin melanoma metastasis biopsy compared with a healthy skin fragment from the same individual. HLA-G protein isoforms other than membrane-bound HLA-G1 protected 1 melanoma cell line from NK lysis. It thus appeared of critical importance to consider the specific role of HLA-G expression in tumors in the design of cancer immunotherapies.
Lila et al. (2000) found HLA-G expression in myocardial biopsies of 5 of 31 heart transplant recipients. HLA-G expression was associated with a decrease of acute and chronic rejection episodes.
Hurks et al. (2001) assayed 11 human uveal melanoma (155720) cell lines and 17 primary uveal melanomas for expression of HLA-G. Because none of the cell lines and none of the primary melanomas expressed HLA-G, the authors concluded that it is unlikely that HLA-G plays a role, direct or indirect, in the modulation of cellular immunity against uveal melanoma tumors.
Using Northern blot analysis and flow cytometry, Wiendl et al. (2002) detected HLA-G mRNA and protein expression in only a minority of glioma cell lines. However, after treatment with IFNG (147570), HLA-G mRNA and protein were expressed in most of these cell lines. Immunohistochemical analysis of brain tumors detected HLA-G expression in nearly all tissue samples examined. Functional assays showed that the presence of HLA-G, either in membrane-bound or soluble form, inhibited effector immune responses and cytolysis by both CD4 (186940)-positive and CD8 (see 186910)-positive T cells. Wiendl et al. (2002) concluded that aberrant expression of HLA-G may contribute to immune escape in human glioblastoma.
Nicolae et al. (2005) pointed out that linkage of asthma (see 600807) and related phenotypes to 6p21 had been reported in 7 genome screens, making it the most replicated region of the genome; however, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci had been difficult. Nicolae et al. (2005) presented evidence from 4 independent samples (Chicago families, Chicago trios, and Hutterite and Dutch families) in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the HLA region on 6p21. They speculated that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.
Using a promoter pull-down assay followed by mass spectrometry analysis, Flajollet et al. (2009) identified RREB1 (602209) as a protein that bound the HLA-G promoter. RREB1 exerted repressive activity on the promoter in HLA-G-negative cells that was mediated by recruitment of HDAC1 (601241) and CTBP1 (602618) and/or CTBP2 (602619). CTBP1 and CTBP2 are subunits of the C-terminal binding protein (CTBP) complex, a corepressor involved in chromatin remodeling. The HLA-G promoter contains 3 RREB1 target sites. Flajollet et al. (2009) proposed that the repressive activity of RREB1 on the HLA-G promoter may be regulated by posttranslational modifications governing its association with CTBP.
HLA-G may modulate the immunologic relationship between mother and fetus in several ways. Hviid et al. (2003) reported an association between certain HLA-G polymorphisms and the mRNA levels of the different alternatively spliced HLA-G isoforms in first trimester trophoblast cell populations. Several alternatively spliced HLA-G mRNA isoforms, including a 14-bp polymorphism in the 3-prime UTR end (exon 8) of the HLA-G gene, are expressed at a significantly lower level than the corresponding HLA-G mRNA isoforms with the 14-bp sequence deleted. Hviid et al. (2003) suggested that this finding may have functional implications in connection with reports of aberrant HLA-G expression and reproductive success.
The HLA-G gene is expressed primarily in placental cells that invade the maternal decidua during pregnancy. This gene encodes multiple isoforms that fulfill a variety of functions at the maternal-fetal interface throughout gestation. A null allele for the most abundant HLA-G isoform was associated with recurrent miscarriage in 2 independent studies (Pfeiffer et al., 2001; Aldrich et al., 2001), suggesting that reduced levels of the HLA-G1 protein may compromise successful pregnancy. Ober et al. (2003) studied whether HLA-G may be associated with fetal loss in women participating in a 15-year prospective study of pregnancy outcome. Overall, this study identified extraordinary levels of variation in the 5-prime-upstream regulatory region of HLA-G and provided evidence for an association between a promoter-region SNP (-725C/G) and fetal loss rates, further attesting to the novel features and critical role of this gene in pregnancy.
Nicolae et al. (2005) found that the risk of asthma in a child is determined both by the child's HLA-G genotype and the mother's affection status. In Chicago families and in a Dutch population, the GG genotype SNP -964G/A in the promoter region of HLA-G was associated with asthma in children of affected mothers, whereas the AA genotype was associated with asthma in children of unaffected mothers. Tan et al. (2007) found the interaction between maternal affection status and child's HLA-G genotype particularly intriguing for 2 reasons: first, maternal asthma remains the most significant and best replicated risk factor for asthma in children (Wright, 2004 and Hoffjan et al., 2005), and second, HLA-G is most highly expressed during pregnancy, when it is thought to play a key role in modulating immune tolerance toward the genetically foreign fetus by enhancing the Th2 arm of the immune system (Hunt et al., 2005). Asthma and allergic disease are also characterized by a skewing toward Th2 immunity. Tan et al. (2007) reported an SNP in the 3-prime untranslated region of HLA-G that influences the targeting of 3 microRNAs (miRNAs) to this gene. They suggested that allele-specific targeting of these miRNAs accounts, at least in part, for earlier observations on HLA-G and the risk of asthma. They concluded that maternal asthma influences children's risk in an allele-specific manner and that the immunosuppressor (Th2-skewing) properties of HLA-G promote asthma pathogenesis.
Rizzo et al. (2006) demonstrated that methotrexate, a folate antagonist used for the treatment of rheumatoid arthritis (RA; 180300), induced the production of soluble HLA-G molecules by increasing IL10 (124092) in cultured peripheral blood mononuclear cells from healthy individuals. Among 156 RA patients, comprising 68 nonresponders and 88 responders to methotrexate treatment, the authors found a significant association between favorable response and lack of the 14-bp polymorphism of HLA-G. The -14/-14 genotype resulted in increased soluble HLA-G and conferred an odds ratio of 2.46 for responsiveness to methotrexate. Rizzo et al. (2006) postulated that the -14/-14 genotype allows the production of adequate levels of the HLA-G antiinflammatory molecule and a consequently positive therapeutic result in RA patients treated with methotrexate.
Bodmer et al. (1990) presented information on a consensus concerning nomenclature of genes in the HLA system.
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Morales, P., Corell, A., Martinez-Laso, J., Martin-Villa, J. M., Varela, P., Paz-Artal, E., Allende, L.-M., Arnaiz-Villena, A. Three new HLA-G alleles and their linkage disequilibria with HLA-A. Immunogenetics 38: 323-331, 1993. [PubMed: 8102125] [Full Text: https://doi.org/10.1007/BF00210473]
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Pfeiffer, K. A., Fimmers, R., Engels, G., van der Ven, H., van der Ven, K. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Molec. Hum. Reprod. 7: 373-378, 2001. [PubMed: 11279300] [Full Text: https://doi.org/10.1093/molehr/7.4.373]
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