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

A splice site mutation converts an inhibitory killer cell Ig-like receptor into an activating one,10.1016/j.molimm.2008.08.270,Molecular Immunology,Je

A splice site mutation converts an inhibitory killer cell Ig-like receptor into an activating one   (Citations: 6)
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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.
Journal: Molecular Immunology - MOL IMMUNOL , vol. 46, no. 4, pp. 640-648, 2009
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    • ...Alleles of Mamu-KIR3DL11, -KIR3DS01, -KIR3DS03, -KIR3DSW07, and -KIR3DSW08 were not obtained in this study and sequences for these genes were taken from GenBank [23,27,30,32]...
    • ...Comprehensive KIR genotyping by pyrosequencing The expanded library of macaque KIR sequences described in this publication and others has enabled the creation of a framework to describe macaque KIRs, and its phylogenetic analysis suggests that the most common KIR genes have been identified [24-28,30,32]...

    Anna J Morelandet al. Characterization of killer immunoglobulin-like receptor genetics and c...

    • ... KIR3DH is the only activating KIR family in this nonhuman primate species, and this family of molecules is highly polymorphic ...

    Ina Hellmannet al. Association of Activating KIR Copy Number Variation of NK Cells with C...

    • ...Furthermore, rhesus macaques possess different types of activating KIR genes compared to human and great apes (Blokhuis et al. 2009a; Hershberger et al. 2001)...
    • ... features of primate KIR3D molecules were found: the inhibitory KIRs show two ITIMs in their cytoplasmic region, whereas the activating KIRs lack these motifs and display a charged amino acid in the transmembrane region, which is in all cases an arginine residue (Fig. 1). Thus, our data confirm and extend previous findings by others that macaque activating KIRs have arginine instead of a lysine residue (Bimber et al. 2008; Blokhuis et al. ...

    Philip H. Kruseet al. Characterization of rhesus macaque KIR genotypes and haplotypes

    • ...Point mutations can lead to single amino acid changes or may have more drastic effects if the polymorphism maps to a splice site, which can result in a change in the overall domain composition of a protein (Blokhuis et al. 2009a)...

    Jeroen H. Blokhuiset al. The mosaic of KIR haplotypes in rhesus macaques

    • ...The ancestral KIR2DL4 gene must have played an essential role in the generation of an array of activating KIRs in rhesus macaques, which were formed by recombination, subsequently followed by a splice site mutation (Blokhuis et al. 2009)...
    • ...This is in contrast to the high levels of polymorphism observed for those domains in other Mamu-KIR genes (Hershberger et al. 2001; Blokhuis et al. 2009)...

    Jeroen H. Blokhuiset al. Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus...

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