Genetic polymorphism in the human LILRB3/LILRA6 locus (118.13)

Abstract

Abstract LILRB3 is an orphan receptor expressed on the surface of myeloid cells. It is structurally distinct from HLA class I binding LILRs and extremely polymorphic in the extracellular domain. LILRB3 can mediate negative signaling through its ITIM-bearing cytoplasmic tail. LILRA6 is identical to LILRB3 in the extracellular part but is potentially an activating receptor. The molecules are encoded by two neighboring genes on human chromosome 19. We have analyzed polymorphism in the LILRB3/A6 locus and found that LILRA6 exhibits a level of polymorphism comparable to LILRB3 with similar polymorphic sites. Moreover, we identified copy number variation (CNV) in the LILRA6 locus with 33% of healthy individuals possessing duplication of LILRA6 and 4% bearing deletion of the gene. Duplications and deletions of LILRA6 and a constant number of LILRB3 seem to be a consequence of unequal crossing-over between the two genes resulting in exchange of the extracellular domains between the receptors. Such exchange explains the maintenance of structural similarity of the two receptors and identity of polymorphic sites. Analysis of mRNA expression in the major PBMC fractions shows that LILRA6 is primarily expressed on monocytes, similarly to LILRB3, and its expression level correlates with the CNV. We suggest that the LILRA6 CNV may influence the ratio of inhibitory vs activating versions of this receptor on the cell surface, potentially affecting the biological consequence of LILRB3/A6 ligation.