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 (GCT͞AGC) 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 Behçet disease, which is known to be associated with HLA-B51. The microsatellite allele consisting of 6 repetitions of GCT͞AGC was present at significantly higher frequency in the patient group (Pc ‫؍‬ 0.00055) than in a control population. Furthermore, the (GCT͞AGC) 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 Behçet disease with MICA rather than HLA-B.

High frequencies of alleles MICA*020 and MICA*027 in Amerindians and evidence of positive selection on exon 3

“…13 The STR consists of (GCT)n repeats, corresponding to alanines in the protein. 14 Eight alleles have been described, A4, A5, A6, A7, A8, A9 and A10, with 4-10 GCT repetitions, and A5.1, which has a G insertion, causing a frame shift mutation that creates a premature In the populations from this study it could also be *00804. In the populations from this study it is MICA*01801.…”

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

“…This evidence begins in the HLA-B locus, where associations between BD and several alleles in addition to HLA-B*51 have been reported (8)(9)(10). It also has been argued that variants in or around MHC class I polypeptide-related sequence A (MICA), the centromeric neighbor of HLA-B that encodes the MHC-I chain-related sequence A, contribute to BD susceptibility (11). However, efforts to parse the effects of MICA and HLA-B alleles definitively have been confounded by their particularly strong LD (11)(12)(13)(14).…”

“…It also has been argued that variants in or around MHC class I polypeptide-related sequence A (MICA), the centromeric neighbor of HLA-B that encodes the MHC-I chain-related sequence A, contribute to BD susceptibility (11). However, efforts to parse the effects of MICA and HLA-B alleles definitively have been confounded by their particularly strong LD (11)(12)(13)(14). Additionally, HLA-A has been identified as a BD susceptibility locus in numerous studies (2,3,(14)(15)(16)(17), and it has been suggested that HLA-C contributes to BD risk, as well (14).…”

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

“…1). Genes within this region have been implicated in the susceptibility to several autoimmune diseases including Behçet's disease, 14,15 Addison's disease, 16 and insulin-dependent diabetes mellitus. 17 MICA and MICB genes encode major histocompatibility complex (MHC)-like molecules with 3 extracellular domains, a transmembrane segment, and a cytoplasmatic tail.…”