Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease

Abstract

A member of a novel family of the human major histocompatibility complex (MHC) class I genes termed MIC (MHC class I chain-related genes), MICA, has been recently identified near the HLA-B gene on the short arm of human chromosome 6. The predicted amino acid sequence of the MICA chain suggests that it folds similarly to typical class I chains and may have the capacity to bind peptides or other short ligands. Therefore, MICA is predicted to have a specialized function in antigen presentation or T cell recognition. During nucleotide sequence analyses of the MICA genomic clone, we found a triplet repeat microsatellite polymorphism of (GCT/AGC)n in the transmembrane (TM) region of the MICA gene. In 68 HLA homozygous B cell lines, 5 distinct alleles of this microsatellite 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 may encode a soluble, secreted form of the MICA molecule. In addition, we have investigated this microsatellite polymorphism in 77 Japanese patients 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.

Figure 1

Genomic organization of the MICA gene and its localization within the HLA region. The MICA gene was localized 46,445 bp centromeric of the HLA-B gene and its orientation was opposite to that of the HLA-B gene, facing to each other in a head-to-head fashion. The MICA gene consisting of 6 exons separated by each intron was spanning 11,720 bp between the HLA-B and BAT1 genes. There were two Alu and one LINE (long interspersed element) sequences in intron 1. Open box on top line indicates the exon and a long open box under the top line indicates the LINE sequence. Black box corresponds to the Alu sequence. Arrow shows the orientation of genes or repetitive sequences.

Figure 2

Microsatellite polymorphism in the TM region (exon 5) of the MICA gene. Alphabetical character under the bracket represents amino acid abbreviation. Dot shows the same nucleotide or amino acid as upper one. Black star shows nucleotide deletion site, and ∗ indicates stop codon.