Subject(s)
Graft vs Host Disease/therapy , Mesenchymal Stem Cell Transplantation , Adolescent , Adult , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Middle Aged , Salvage Therapy/methods , Steroids/therapeutic use , Transplantation, Homologous/adverse effects , Young AdultABSTRACT
HLA-G is expected to play an important role during fetal development. Recently, a healthy individual homozygous for the HLA-G*0105N allele has been described, suggesting that HLA-G expression was not essential for fetal survival. We now report studies of one family with five healthy siblings homozygous for HLA-G*0105N, who had been normally delivered; three of these siblings were females who also had normal deliveries. In addition, HLA-G*0105N cDNA has been fully sequenced, and normal G1 membrane anchored protein cannot be translated since after the codon 130 cytosine deletion (exon 3) a reading frameshift is observed leading to the existence of premature stop codon at position 189 (beginning of exon 4). Other protein isoforms (G2, G3 and G6), all containing the leader peptide and the alpha1 domain, are possible and their messenger mRNAs were found; any of these may undertake the necessary HLA-G functions. Our data show that the membrane anchored HLA-G molecule is not necessary in either mother or fetus for a normal pregnancy and survival. Also, individuals homozygous for HLA-G*0105N are healthy and with no indications of immunodeficiency or autoimmunity.
Subject(s)
HLA Antigens/genetics , HLA Antigens/immunology , HLA Antigens/physiology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/physiology , Homozygote , Alleles , Alternative Splicing , Base Sequence , DNA, Complementary , Family Health , Female , HLA-A Antigens/genetics , HLA-B Antigens/genetics , HLA-B13 Antigen , HLA-C Antigens/immunology , HLA-G Antigens , Haplotypes , Histocompatibility Antigens Class I/immunology , Humans , Male , Molecular Sequence Data , Pedigree , Polymorphism, Restriction Fragment Length , Protein Isoforms/genetics , Protein Isoforms/immunology , RNA, Messenger/genetics , Sequence Alignment , Sequence Deletion , HLA-E AntigensABSTRACT
MHC-G is a class Ib (non-classical) major histocompatibility complex (MHC) whose functional and evolutionary characteristics are still under scrutiny. The study of noncoding sequences in the MHC genes may provide important phylogenetic information. In this work we have sequenced the MHC-G exon 8, which encodes for the 3'UT region, in different species of primates. It has been shown that: (1) a previously described 14 base pair (bp) deletion polymorphism is human-specific and the HLA-G alleles may be classified according to its absence or presence; (2) another newly described 3 bp deletion/insertion polymorphism is also human-specific; and (3) another newly described 51 bp deletion polymorphism is common to Pongidae and humans, but is not found in other primates belonging to the Cercopithecinae family. A hypothesis on the evolutionary pathway of this gene is put forward in the light of these findings.
Subject(s)
3' Untranslated Regions , Evolution, Molecular , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Polymorphism, Genetic , Primates/genetics , Animals , Base Sequence , Exons , HLA-G Antigens , Humans , Molecular Sequence Data , Phylogeny , Sequence DeletionABSTRACT
HLA-G is a class Ib (nonclassical) major histocompatibility complex (MHC) protein expressed at the materno-fetal interface that may inhibit natural killer (NK) cell-mediated lysis in an allotype-independent manner. The human MHC-G transcript is differentially spliced, giving rise to at least six different forms. In order to study the evolutionary importance of this phenomenon, the presence of alternative splicing in MHC-G mRNA molecules from Pongidae (Chimpanzee, Gorilla, and Orangutan) has been investigated in the present work, and three alternative spliced isoforms (i.e.: G1, G2, and G3) have been found, but not the G4 and the soluble G5 and G6 ones. In addition, a novel MHC-G isoform is described in Gorilla, "G2 short." This molecule is similar to the G2 isoform, but it lacks 29 amino acids normally encoded by exon 4. Our findings suggest that soluble isoforms are not necessary for MHC-G function(s) in Pongidae or that MHC-G is not a functional protein, because G1 is not necessary for survival in humans and Cercopithecinae bear stop codons in MHC-G exon 3.
