A splice site mutation converts an inhibitory killer cell Ig-like receptor into an activating one.

The killer cell Ig-like receptor (KIR) 3DH protein in rhesus macaques (Macaca mulatta) is thought to be an activating one because it contains a charged arginine in its transmembrane domain and has a truncated cytoplasmic domain. MmKIR3DH has thus far been characterized by an analysis of cDNA. Its presence and polymorphism has been further investigated by examining mRNA transcripts and genomic sequences in families. Multiple copies of MmKIR3DH are present per animal, suggesting that the gene has been duplicated on some haplotypes. All transcripts are truncated and lack exon 8. Investigation of the gene itself shows that exon 8 is present, intact, and homologous to MmKIR2DL4. However, there is a mutation in the donor splice site of intron 8, which is absent in MmKIR2DL4 genomic sequences. This mutation introduces a frameshift, subsequently resulting in a premature stopcodon. To further verify this mutation, a cohort of unrelated animals from different geographical locations was examined, and both exon 8 and the splice site mutation were seen to be present in their MmKIR3DH genes. The data suggest that the splice site mutation causes the truncation of the MmKIR3DH transcript and the subsequent loss of its inhibitory motifs further downstream. Loss of inhibitory potential through different mutations is observed in other primate species as well, suggesting convergent evolution; however, this is the first report to document that a mutation in an intron produces a similar effect.