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Genetics of the P2X7 receptor and human disease

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Abstract

The P2RX7 gene is highly polymorphic, and many single nucleotide polymorphisms (SNPs) underlie the wide variation observed in P2X7 receptor responses. We review the discovery of those non-synonymous SNPs that affect receptor function and compare their frequencies in different ethnic populations. Analysis of pairwise linkage disequilibrium (LD) predicts a limited range of haplotypes. The strong LD between certain functional SNPs provides insight into published studies of the association between SNPs and human disease.

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References

  1. International Human Genome Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431(7011):931–45

    Article  Google Scholar 

  2. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437(7063):1299–1320

    Article  Google Scholar 

  3. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62(3):676–689

    Article  PubMed  CAS  Google Scholar 

  4. Burn J, Chapman P, Delhanty J, Wood C, Lalloo F, Cachon-Gonzalez MB et al (1991) The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. J Med Genet 28(5):289–296

    Article  PubMed  CAS  Google Scholar 

  5. The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678

    Article  Google Scholar 

  6. Buell GN, Talabot F, Gos A, Lorenz J, Lai E, Morris MA et al (1998) Gene structure and chromosomal localization of the human P2X7 receptor. Receptors Channels 5(6):347–354

    PubMed  CAS  Google Scholar 

  7. Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S et al (2001) A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem 276(14):11135–11142

    Article  PubMed  CAS  Google Scholar 

  8. Boldt W, Klapperstuck M, Buttner C, Sadtler S, Schmalzing G, Markwardt F (2003) Glu496Ala polymorphism of human P2X7 receptor does not affect its electrophysiological phenotype. Am J Physiol Cell Physiol 284(3):C749–C756

    PubMed  CAS  Google Scholar 

  9. Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML et al (2003) An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem 278(19):17108–17113

    Article  PubMed  CAS  Google Scholar 

  10. Smart ML, Gu B, Panchal RG, Wiley J, Cromer B, Williams DA et al (2003) P2X7 receptor cell surface expression and cytolytic pore formation are regulated by a distal C-terminal region. J Biol Chem 278(10):8853–8860

    Article  PubMed  CAS  Google Scholar 

  11. Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP, Fuller SJ et al (2004) An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor. J Biol Chem 279(30):31287–31295

    Article  PubMed  CAS  Google Scholar 

  12. Skarratt KK, Fuller SJ, Sluyter R, Dao-Ung LP, Gu BJ, Wiley JS (2005) A 5′ intronic splice site polymorphism leads to a null allele of the P2X7 gene in 1–2% of the Caucasian population. FEBS Lett 579(12):2675–2678

    Article  PubMed  CAS  Google Scholar 

  13. Shemon AN, Sluyter R, Fernando SL, Clarke AL, Dao-Ung LP, Skarratt KK et al (2006) A Thr357 to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X7 function and impairs ATP-induced mycobacterial killing by macrophages. J Biol Chem 281(4):2079–2086

    Article  PubMed  CAS  Google Scholar 

  14. Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P et al (2005) A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J Immunol 175(1):82–89

    PubMed  CAS  Google Scholar 

  15. Denlinger LC, Coursin DB, Schell K, Angelini G, Green DN, Guadarrama AG et al (2006) Human P2X7 pore function predicts allele linkage disequilibrium. Clin Chem 52(6):995–1004

    Article  PubMed  CAS  Google Scholar 

  16. Barden N, Harvey M, Gagne B, Shink E, Tremblay M, Raymond C et al (2006) Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 141B(4):374–382

    Article  PubMed  CAS  Google Scholar 

  17. Lucae S, Salyakina D, Barden N, Harvey M, Gagne B, Labbe M et al (2006) P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum Mol Genet 15(16):2438–2445

    Article  PubMed  CAS  Google Scholar 

  18. McQuillin A, Bass NJ, Choudhury K, Puri V, Kosmin M, Lawrence J, et al (2008) Case–ontrol studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders. Mol Psychiatry. doi:1038/mp.2008.6

  19. Saunders BM, Fernando SL, Sluyter R, Britton WJ, Wiley JS (2003) A loss-of-function polymorphism in the human P2X7 receptor abolishes ATP-mediated killing of mycobacteria. J Immunol 171(10):5442–5446

    PubMed  CAS  Google Scholar 

  20. Fairbairn IP, Stober CB, Kumararatne DS, Lammas DA (2001) ATP-mediated killing of intracellular mycobacteria by macrophages is a P2X(7)-dependent process inducing bacterial death by phagosome–lysosome fusion. J Immunol 167(6):3300–3307

    PubMed  CAS  Google Scholar 

  21. Kusner DJ, Adams J (2000) ATP-induced killing of virulent Mycobacterium tuberculosis within human macrophages requires phospholipase D. J Immunol 164(1):379–388

    PubMed  CAS  Google Scholar 

  22. Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H, Marks GB et al (2007) A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am J Respir Crit Care Med 175(4):360–366

    Article  PubMed  CAS  Google Scholar 

  23. Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS (1997) ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 7(3):433–444

    Article  PubMed  CAS  Google Scholar 

  24. Nino-Moreno P, Portales-Perez D, Hernandez-Castro B, Portales-Cervantes L, Flores-Meraz V, Baranda L et al (2007) P2X7 and NRAMP1/SLC11 A1 gene polymorphisms in Mexican mestizo patients with pulmonary tuberculosis. Clin Exp Immunol 148(3):469–477

    PubMed  CAS  Google Scholar 

  25. Coutinho-Silva R, Stahl L, Raymond MN, Jungas T, Verbeke P, Burnstock G et al (2003) Inhibition of chlamydial infectious activity due to P2X7R-dependent phospholipase D activation. Immunity 19(3):403–412

    Article  PubMed  CAS  Google Scholar 

  26. Coutinho-Silva R, Perfettini JL, Persechini PM, Dautry-Varsat A, Ojcius DM (2001) Modulation of P2Z/P2X(7) receptor activity in macrophages infected with Chlamydia psittaci. Am J Physiol Cell Physiol 280(1):C81–C89

    PubMed  CAS  Google Scholar 

  27. Panupinthu N, Rogers JT, Zhao L, Solano-Flores LP, Possmayer F, Sims SM et al (2008) P2X7 receptors on osteoblasts couple to production of lysophosphatidic acid: a signaling axis promoting osteogenesis. J Cell Biol 181(5):859–871

    Article  PubMed  CAS  Google Scholar 

  28. Ohlendorff SD, Tofteng CL, Jensen JE, Petersen S, Civitelli R, Fenger M et al (2007) Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment. Pharmacogenet Genomics 17(7):555–567

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Nepean Clinical School, Nepean Hospital, University of Sydney, Penrith, NSW, 2750, Australia

    Stephen J. Fuller, Leanne Stokes, Kristen K. Skarratt, Ben J. Gu & James S. Wiley

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  1. Stephen J. Fuller
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  2. Leanne Stokes
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  3. Kristen K. Skarratt
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  4. Ben J. Gu
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  5. James S. Wiley
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Correspondence to James S. Wiley.

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Fuller, S.J., Stokes, L., Skarratt, K.K. et al. Genetics of the P2X7 receptor and human disease. Purinergic Signalling 5, 257–262 (2009). https://doi.org/10.1007/s11302-009-9136-4

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  • DOI: https://doi.org/10.1007/s11302-009-9136-4

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