TRIPLET REPEAT POLYMORPHISM IN THE TRANSMEMBRANE REGION OF THE MICA GENE - A STRONG ASSOCIATION OF 6 GCT REPETITIONS WITH BEHCET-DISEASE

A member of a novel family of the human major histocompatibility compl ex (MHC) class I genes termed MIC (MHC class I chain-related genes), M ICA, has been recently identified near the HLA-B gene on tile short ar m of human chromosome 6. The predicted amino acid sequence of the MICA chain suggests that it folds similarly to typical class I chains and mag have the capacity to bind peptides or other short ligands. Therefo re, MICA is predicted to have a specialized function in antigen presen tation or T cell recognition. During nucleotide sequence analyses of t he MICA genomic clone, we found a triplet repeat microsatellite polymo rphism of (GCT/AGC)(n) in the transmembrane (TM) region of the MICA ge ne. In 68 HLA homozygous B cell lines, 5 distinct alleles of this micr osatellite sequence were detected. One of them contained an additional one base insertion that created a frameshift mutation resulting in a premature termination codon in the TM region. This particular allele m ag encode a soluble, secreted Form of the MICA molecule. In addition, we have investigated this microsatellite polymorphism in 77 Japanese p atients with Behcet disease, which is known to be associated with HLA- B51. The microsatellite allele consisting of 6 repetitions of GCT/AGC was present at significantly higher frequency in the patient group (Pc = 0.00055) than in a control population. Furthermore, the (GCT/AGC)(6 ) allele was present in all B51 positive patients and in an additional 13 B51 negative patients. These results suggest the possibility of a primary association of Behcet disease with MICA rather than HLA-B.