Genes encoding human killer-cell Ig-like receptors with D1 and D2 extracellular domains all contain untranslated pseudoexons encoding a third Ig-like domain

Human killer-cell immunoglobulin-like receptors (KIR) show three types of organization of their extracellular domains: D0-D1-D2 in KIR3D, D1-D2 in the majority of KIR2D, and D0-D2 in KIR2DL4 and the novel KIR2DL5. The gene for a KIR2DL3 variant, which has a D1-D2 structure, has been shown previously to have a nonexpressed region (pseudoexon 3) that is paralogous to the exon encoding the D0 domain of other KIR. This pseudoexon is not expressed because it is skipped during splicing of pre-mRNA. In this study, we demonstrate that all eight genes encoding human KIR with D1-D2 configuration (KIR2DL1-KIR2DL3, KIR2DS1-KIR2DS5) have similarly untranslated pseudoexons. Whereas the pseudoexons of four of these KIR genes bear nonsense mutations and/or altered splicing sites, the pseudoexons in the other four KIR genes have no major structural abnormalities, indicating that other mechanisms are responsible for inactivation of their exons 3. A comparison of the sequences on pseudoexons 3 with the paralogous expressed exons suggests that an exonic splicing enhancer may be necessary for the expression of exon 3 in KIR genes.