Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletion in the general population

Abstract

CD94 and NKG2 are members of the NK cell receptor families, and are encoded in the natural killer gene complex (NKC) on human chromosome 12p12-13, one of the candidate chromosomal regions for rheumatic diseases. To examine a possible association between variations in CD94 and NKG2 genes and genetic susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), we carried out a systematic polymorphism screening of NKG2-A (KLRC1), NKG2-C (KLRC2) and CD94 (KLRD1) genes on a population basis. In NKG2-A, previously considered to be highly conserved, 10 polymorphisms in the noncoding region and introns, as well as one rare variation leading to an amino acid substitution within the transmembrane region, c.238T4A (Cys80Ser), were detected. In NKG2-C, in addition to the previously described two nonsynonymous substitutions, c.5G4A (Ser2Asn) and c.305C4T (Ser102Phe), two polymorphisms were newly detected in the noncoding region. In CD94, only one single nucleotide substitution was identified in the 5 0 untranslated region. When the patients and healthy individuals were genotyped for these variations, no significant association was observed. However, although statistically not significant, NKG2-A c.238T4A (Cys80Ser) was observed in three patients with RA, but in none of the healthy individuals and the patients with SLE. Unexpectedly, in the process of polymorphism screening, we identified homozygous deletion of NKG2-C in approximately 4.3% of healthy donors; under the assumption of Hardy-Weinberg equilibrium, the allele frequency of NKG2-C deletion was estimated to be 20.7%. These results demonstrated that, although human NKG2-A, -C and CD94 are generally conserved with respect to amino acid sequences, NKG2-A is polymorphic in the noncoding region, and that the number of genes encoded in the human NKC is variable among individuals, as previously shown for the leukocyte receptor complex (LRC), HLA and Fcg receptor (FCGR) regions.

Determination of gene organization in the human IGHV region on single chromosomes

“…As a relevant comparison, many other immunity-related multigene families such as the human Ig lambda chain constant region (IGLC), 35,36 Ig kappa chain variable region (IGKV), 37 T-cell receptor gamma chain variable, joining and constant regions (TRGV, TRGJ, and TRGC), 38,39 human leukocyte antigens (HLA), 40,41 killer-cell IG-like receptor (KIR), 42 and natural killer gene complex 43 also display varying numbers of some genes. Allelic deletions and duplications involving one or more genes were exhaustively studied in the Ig heavy chain constant region.…”

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

“…These data imply that NKG2C is dispensable at least for reproduction and survival (22)(23)(24). Nevertheless, the impact of NKG2C genotype on NK cell maturation, receptor repertoire, and function in response to HCMV infection remains to be defined.…”

Pas de deux: Natural Killer Receptors and MHC Class I Ligands in Primates

“…The CD94 and NKG2D genes are monomorphic in the primate species tested, except for the orangutan where polymorphisms have been reported for the CD94 gene [60]. For the activating receptor genes NKG2C allelic polymorphism have been identified in primates [61][62][63]. Although the general genomic organisation of the CD94 to LY49L interval appears to be conserved in primates, particularly the activating receptor genes appear to be subject of duplications (Fig.…”