KIR And HLA Haplotype Analysis in a Family Lacking The KIR 2DL1-2DP1 Genes

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Abstract

The killer cell immunoglobulin-like receptor (KIR) gene cluster exhibits extensive allelic and haplotypic diversity that is observed as presence/absence of genes, resulting in expansion and contraction of KIR haplotypes and by allelic variation of individual KIR genes. We report a case of KIR pseudogene 2DP1 and 2DL1 gene absence in members of one family with the children suffering from acute myelogenous leukemia (AML). Killer cell immunoglo-bulin-like receptor low resolution genotyping was performed by the polymerase chain reaction (PCR)-sequencespecific primers (SSP)/sequence-specific oligonucleotide (SSO) method and haplotype assignment was done by gene content analysis. Both parents and the maternal grandfather, shared the same Cen-B2 KIR haplotype, containing KIR 3DL3, -2DS2, -2DL2 and -3DP1 genes. The second haplotype in the KIR genotype of the mother and grandfather was Tel-A1 with KIR 2DL4 (normal and deleted variant), -3DL1, -22 bp deletion variant of the 2DS4 gene and -3DL2, while the second haplotype in the KIR genotype of the father was Tel-B1 with 2DL4 (normal variant), -3DS1, -2DL5, -2DS5, -2DS1 and 3DL2 genes. Haplotype analysis in all three offsprings revealed that the children inherited the Cen-B2 haplotype with the same gene content but two of the children inherited a deleted variant of the 2DL4 gene, while the third child inherited a normal one. The second haplotype of all three offspring contained KIR 2DL4, -2DL5, -2DS1, -2DS4 (del 22bp variant), -2DS5, -3DL1 and -3DL2 genes, which was the basis of the assumption that there is a hybrid haplotype and that the present 3DL1 gene is a variant of the 3DS1 gene. Due to consanguinity among the ancestors, the results of KIR segregation analysis showed the existence of a very rare KIR genotype in the offspring. The family who is the subject of this case is even more interesting because the father was 10/10 human leukocyte antigen (HLA)-matched to his daughter, all members of the family have the “best” donor KIR-B content and the presence of a rare KIR genotype with KIR 2DP1-2DL1 genes absence.

1. Rajalingam R. Human diversity of killer cell immunoglobulin-like receptors and disease. Korean J Hematol. 2011; 46(4): 216-228.

2. Jiang W, Johnson C, Jayaraman J, Simecek N, Noble J, Moffatt MF, et al. Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res. 2012; 22(10): 1845-1854.

3. Hou L, Chen M, Ng J, Hurley CK. Conserved KIR allele-level haplotypes are altered by microvariation in individuals with European ancestry. Genes Immun. 2012; 13(1): 47-58.

4. Gardiner CM, Guethlein LA, Shilling HG, Pando M, Carr WH, Rajalingam R, et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR 3DL1 gene polymorphism. J Immunol. 2001; 166(5): 2992-3001.

5. Trowsdale J, Barten R, Haude A, Stewart CA, Beck S, Wilson MJ. The genomic context of natural killer receptor extended gene families. Immunol Rev. 2001; 181(1): 20-38.

6. Li H, Pascal V, Martin MP, Carrington M, Anderson SK. Genetic control of variegated KIR gene expression: Polymorphisms of the bi-directional KIR3DL1 promoter are associated with distinct frequencies of gene expression. PLoS Genet. 2008; 4(11): e1000254. doi: 10.1371/journal.pgen.1000254.

7. Ludajic K, Balavarca Y, Bickeböller H, Rosenmayr A, Fae I, Fischer GF, et al. KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation. Bone Marrow Transplant. 2009; 44(2): 97-103.

8. Pyo C-W, Guethlein LA, Pyo QV, Wang R, Abi- Rached L, Norman PJ, et al. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS ONE. 2010; 5(12): e15115. doi: 10.1371/journal. pone.0015115.

9. Shilling HG, Guethlein LA, Cheng NW, Gardiner CM, Rodriguez R, Tyan D, et al. Allelic polymorphism synergizes with variable gene content to individualize human KIR genotype. J Immunol. 2002; 168(5): 2307-2315.

10. Middleton D, Meenagh A, Gourraud PA. KIR haplotype content at the allele level in 77 Northern Irish families. Immunogenetics. 2007; 59(2): 145-158.

11. Garcia CA, Robinson J, Guethlein LA, Parham P, Madrigal JA, Marsh SG. Human KIR sequences 2003. Immunogenetics. 2003; 55(4): 227-239.

12. Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D, et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA. 2000; 97(9): 4778-4783.

13. Hsu KC, Chida S, Dupont B, Geraghty DE. The killer cell immunoglobulin-like receptor (KIR) genomic region: Gene-order, haplotypes and allelic polymorphism. Immunol Rev. 2002; 190: 40-52.

14. Gourraud PA, Meenagh A, Cambon-Thomsen A, Middleton D. Linkage disequilibrium organization of the human KIR superlocus: Implications for KIR data analyses. Immunogenetics. 2010; 62(11-12): 729-740.

15. Becker S, Tonn T, Füssel T, Uhrberg M, Bogdanow M, Seifried E, et al. Assessment of killer cell immunoglobulin-like receptor expression and corresponding HLA class I phenotypes demonstrates heterogenous KIR expression independent of anticipated HLA class I ligands. Hum Immunol. 2003; 64(2): 183-193.

16. Niokou D, Spyropoulou-Vlachou M, Darlamitsou A, Stavropoulos-Giokas C. Distribution of killer cell immunoglobulin-like receptors in the Greek population. Hum Immunol. 2003; 64(12): 1167-1176.

17. Bontadini A, Testi M, Cuccia MC, Martinetti M, Carcassi C, Chiesa A, et al. Distribution of killer cell immunoglobulin-like receptors genes in the Italian Caucasian population. J Transl Med. 2006; 4(1): 44-53.

18. Gutiérrez-Rodríguez ME, Sandoval-Ramнrez L, Díaz-Flores M, Marsh SG, Valladares-Salgado A, Madrigal JA, et al. KIR gene in ethnic and Mestizo populations from Mexico. Hum Immunol. 2006; 67(1-2): 85-93.

19. Pavlova Y, Kolesar L, Striz I, Jabor A, Slavcev A. Distribution of KIR genes in the Czech population. Int J Immunogenet. 2008; 35(1): 57-61.

20. Velickovic M, Velickovic Z, Panigoro R, Dunckley H. Diversity of killer cell immunoglobulin- like receptor genes in Indonesian populations of Java, Kalimantan, Timor and Irian Jaya. Tissue Antigens. 2009; 73(1): 9-16.

21. Augusto DG, Piovezan BZ, Tsuneto LT, Martin MP, Carrington M, Petzl-Erleret ML. Diversity of the KIR gene cluster in an urban Brazilian population. Immunogenetics. 2012; 64(2): 143-152.

22. Constantinescu I, Nedelcu FD, Toader MA, Vasile D, Zaharia M, Harza M, et al. Evaluation of KIR genotypes and cytokine gene polymorphism in Romanian kidney transplant recipients: Impact on acute and chronic allograft rejection. Tissue Antigens. 2006; 67(6): 505-506.

23. Djulejić E, Trajkov D, Petlichkovski A, Hristomanova S, Middleton D, Spiroski M. Distribution of killer cell immunoglobulin-like receptors in the Macedonian population. Hum Immunol. 2010; 7(3): 281-288.

24. Kamenarić Burek M, Grubić Z, Stingl K, Žunec R. Distribution of KIR genes in the Croatian population. Hum Immunol. 2013; 74(8): 952-956.

25. Single RM, Martin MP, Gao X, Meyer D, Yeager M, Kidd JR, et al. Global diversity and evidence for coevolution of KIR and HLA. Nat Genet. 2007; 39(9): 1114-1119.

26. Lee YC, Chan SH, Ren EC. Asian population frequencies and haplotype distribution of killer cell immu-noglobulin-like receptor (KIR) genes among Chinese, Malay, and Indian in Singapore. Immunogenetics. 2008; 60(11): 645-654.

27. Middleton D, Meenagh A, Moscoso J, Arnaiz- Villena A. Killer immunoglobulin receptor gene and allele frequencies in Caucasoid, Oriental and Black populations from different continents. Tissue Antigens. 2008; 71(2): 105-113.

28. Wende H, Volz A, Ziegler A. Extensive gene duplications and a large inversion characterize the human leukocyte receptor cluster. Immunogenetics. 2000; 51(8-9): 703-713.

29. Martin MP, Bashirova A, Traherne J, Trowsdale J, Carrington M. Cutting edge: Expansion of the KIR locus by unequal crossing over. J Immunol. 2003; 171(5): 2192-2195.

30. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010; 116(4): 2411-2419.

31. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: A database and online repository for immune gene frequencies in worldwide populations Nucleic Acids Res. 2011; 39(Database issue): D913-D919.

32. Norman JP, Abi-Rached L, Gendzekhadze K, Hammond JA, Moesta AK, Sharma D, et al. Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes. Genome Res. 2009; 19(5): 757-769.

33. Norman PJ, Abi-Rached L, Gendzekhadze K, Korbel D, Gleimer M, Rowley D, et al. Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans. Nat Genet. 2007; 39(9): 1092-1099.

Balkan Journal of Medical Genetics

The Journal of Macedonian Academy of Sciences and Arts

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