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

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.238T>A (Cys80Ser), were detected. In NKG2-C, in addition to the previously described two nonsynonymous substitutions, c.5G>A (Ser2Asn) and c.305C>T (Ser102Phe), two polymorphisms were newly detected in the noncoding region. In CD94, only one single nucleotide substitution was identified in the 5' 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.238T>A (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 Fcgamma receptor (FCGR) regions.