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HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.[5]

Protein HLA-G PDB 1ydp.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesHLA-G, MHC-G, major histocompatibility complex, class I, G
External IDsMGI: 95915 HomoloGene: 133255 GeneCards: HLA-G
Gene location (Human)
Chromosome 6 (human)
Chr.Chromosome 6 (human)[1]
Chromosome 6 (human)
Genomic location for HLA-G
Genomic location for HLA-G
Band6p22.1Start29,826,967 bp[1]
End29,831,125 bp[1]
RNA expression pattern
PBB GE HLA-G 211529 x at fs.png

PBB GE HLA-G 211528 x at fs.png

PBB GE HLA-G 210514 x at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 6: 29.83 – 29.83 MbChr 17: 37.27 – 37.27 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail.[5] Exon 7 and 8 are not translated due to a stop codon present in exon 6.[6]



HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not.[7] As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss.[8] its downregulation is related to HLA-A and -B downregulation results in protection from cytotoxic T cell responses, but would in theory result in a missing self response by natural killer cells. HLA-G is a ligand for NK cell inhibitory receptor KIR2DL4, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.[9]

However, a large family with several members bearing only "null" HLA-G alleles has been found. None of these homozygous subjects have pregnancy or birth difficulties; nor do they present immunodeficiencies, autoimmune diseases, or tumors.[10][11] It is striking that this "null" allele (HLA-G*01:05N), while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations.[12] Also, some higher primates do not show all MHC-G isoforms.[13] In addition, Cercopithecinae middle-sized Old World monkeys do not bear full MHC-G molecules since all of these monkeys present stop codons at MHC-G DNA.[14] All of these anomalies must be studied.

The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos.[15] However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.[15]


HLA-G has been shown to interact with CD8A.[16][17]


  1. ^ a b c ENSG00000233095, ENSG00000237216, ENSG00000276051, ENSG00000204632, ENSG00000235346, ENSG00000235680, ENSG00000206506 GRCh38: Ensembl release 89: ENSG00000230413, ENSG00000233095, ENSG00000237216, ENSG00000276051, ENSG00000204632, ENSG00000235346, ENSG00000235680, ENSG00000206506 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000016206 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ a b "Entrez Gene: HLA-G HLA-G histocompatibility antigen, class I, G".
  6. ^ Castelli, Erick C.; Mendes-Junior, Celso T.; Veiga-Castelli, Luciana C.; Roger, Michel; Moreau, Philippe; Donadi, Eduardo A. (2011-11-01). "A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution". Molecular Biology and Evolution. 28 (11): 3069–3086. doi:10.1093/molbev/msr138. ISSN 0737-4038. PMID 21622995.
  7. ^ Jay Iams; Creasy, Robert K.; Resnik, Robert; Robert Reznik (2004). Maternal-fetal medicine. Philadelphia: W.B. Saunders Co. pp. 31–32. ISBN 978-0-7216-0004-8.
  8. ^ Michita, Rafael Tomoya; Zambra, Francis Maria Báo; Fraga, Lucas Rosa; Sanseverino, Maria Teresa Vieira; Callegari-Jacques, Sidia Maria; Vianna, Priscila; Chies, José Artur Bogo (2016). "A tug-of-war between tolerance and rejection – New evidence for 3′UTR HLA-G haplotypes influence in recurrent pregnancy loss". Human Immunology. 77 (10): 892–897. doi:10.1016/j.humimm.2016.07.004. PMID 27397898.
  9. ^ Lash, G, Robson, S, Bulmer, J. (2010). "Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua". Placenta. 31 (S): 87–92. doi:10.1016/j.placenta.2009.12.022. PMID 20061017.CS1 maint: Multiple names: authors list (link)
  10. ^ Suárez MB, Morales P, Castro MJ, Fernández V, Varela P, Alvarez M, Martínez-Laso J, Arnaiz-Villena A (1997). "A new HLA-G allele (HLA-G*0105N) and its distribution in the Spanish population". Immunogenetics. 45 (6): 464–5. doi:10.1007/s002510050235. PMID 9089111.
  11. ^ Casro MJ, Morales P, Rojo-Amigo R, Martinez-Laso J, Allende L, Varela P, Garcia-Berciano M, Guillen-Perales J, Arnaiz-Villena A (September 2000). "Homozygous HLA-G*0105N healthy individuals indicate that membrane-anchored HLA-G1 molecule is not necessary for survival". Tissue Antigens. 56 (3): 232–9. doi:10.1034/j.1399-0039.2000.560305.x. PMID 11034559.
  12. ^ Arnaiz-Villena A, Enriquez-de-Salamanca M, Areces C, Alonso-Rubio J, Abd-El-Fatah-Khalil S, Fernandez-Honrado M, Rey D (April 2013). "HLA-G(∗)01:05N null allele in Mayans (Guatemala) and Uros (Titikaka Lake, Peru): Evolution and population genetics". Hum. Immunol. 74 (4): 478–82. doi:10.1016/j.humimm.2012.12.013. PMID 23261410.
  13. ^ Castro MJ, Morales P, Martinez-Laso J, Allende L, Rojo-Amigo R, Gonzalez-Hevilla M, Varela P, Moscoso J, Garcia-Berciano M, Arnaiz-Villena A (November 2000). "Lack of MHC-G4 and soluble (G5, G6) isoforms in the higher primates, Pongidae". Hum. Immunol. 61 (11): 1164–8. doi:10.1016/s0198-8859(00)00189-0. PMID 11137222.
  14. ^ Castro MJ, Morales P, Fernández-Soria V, Suarez B, Recio MJ, Alvarez M, Martín-Villa M, Arnaiz-Villena A (1996). "Allelic diversity at the primate Mhc-G locus: exon 3 bears stop codons in all Cercopithecinae sequences". Immunogenetics. 43 (6): 327–36. doi:10.1007/bf02199801. PMID 8606053.
  15. ^ a b Rebmann V, Switala M, Eue I, Grosse-Wilde H (May 2010). "Soluble HLA-G is an independent factor for the prediction of pregnancy outcome after ART: a German multi-centre study". Hum Reprod. 25 (7): 1691–8. doi:10.1093/humrep/deq120. PMID 20488801.
  16. ^ Gao GF, Willcox BE, Wyer JR, Boulter JM, O'Callaghan CA, Maenaka K, Stuart DI, Jones EY, Van Der Merwe PA, Bell JI, Jakobsen BK (May 2000). "Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha". J. Biol. Chem. 275 (20): 15232–8. doi:10.1074/jbc.275.20.15232. PMID 10809759.
  17. ^ Sanders SK, Giblin PA, Kavathas P (September 1991). "Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts". J. Exp. Med. 174 (3): 737–40. doi:10.1084/jem.174.3.737. PMC 2118947. PMID 1908512.

Further readingEdit