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J. Biol. Chem., Vol. 281, Issue 4, 2079-2086, January 27, 2006

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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^*

Anne N. Shemon, Ronald Sluyter, Suran L. Fernando, Alison L. Clarke¶, Lan-Phuong Dao-Ung, Kristen K. Skarratt, Bernadette M. Saunders||, Khai See Tan¶, Ben J. Gu, Stephen J. Fuller, Warwick J. Britton||, Steven Petrou¶, and James S. Wiley1

From the Department of Medicine, University of Sydney, Level 5, Spurrett Building, Nepean Hospital, Penrith, New South Wales 2750, the Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales 2042, the ^||Discipline of Medicine, Central Clinical School, University of Sydney, Sydney, New South Wales 2006, and the ^¶Howard Florey Institute, University of Melbourne, Victoria 3010, Australia

The P2X₇ receptor is a ligand-gated cation channel that is highly expressed on mononuclear leukocytes and that mediates ATP-induced apoptosis and killing of intracellular pathogens. There is a wide variation in P2X₇ receptor function between subjects, explained in part by four loss-of-function polymorphisms (R307Q, E496A, I568N, and a 5'-intronic splice site polymorphism), as well as rare mutations. In this study, we report the allele frequencies of 11 non-synonymous P2X₇ polymorphisms and describe a fifth loss-of-function polymorphism in the gene (1096C G), which changes Thr³⁵⁷ to Ser (T357S) with an allele frequency of 0.08 in the Caucasian population. P2X₇ function was measured by ATP-induced ethidium⁺ influx into peripheral blood lymphocytes and monocytes and, when compared with wild-type subjects, was reduced to 10–65% in heterozygotes, 1–18% in homozygotes, and 0–10% in compound heterozygotes carrying T357S and a second loss-of-function polymorphism. Overexpression of the T357S mutant P2X₇ in either HEK-293 cells or Xenopus oocytes gave P2X₇ function of 50% that of wild-type constructs. Differentiation of monocytes to macrophages, which also up-regulates P2X₇, restored P2X₇ function to near normal in cells heterozygous for T357S and to a value 50–65% of wild-type in cells homozygous for T357S or compound heterozygous for T357S/E496A. However, macrophages from subjects that are compound heterozygous for either T357S/R307Q or T357S/stop codon had near-to-absent P2X₇ function. These functional deficits induced by T357S were paralleled by impaired ATP-induced apoptosis and mycobacteria killing in macrophages from these subjects. Lymphocytes, monocytes, and macrophages from subjects homozygous for T357S or compound heterozygous for T357S and a second loss-of-function allele have reduced or absent P2X₇ receptor function.

Received for publication, July 19, 2005 , and in revised form, October 13, 2005.

^* This work was supported by the National Health and Medical Research Council of Australia, the Leukemia Foundation of New South Wales, the Community Health Anti Tuberculosis Association, the Cecilia Kilkeary Foundation, the New South Wales Department of Health, a Faculty of Medicine Postgraduate Award (to A. N. S.) from the University of Sydney, a National Health and Medical Research Council of Australia Postgraduate Award (to S. L. F.), and a Sesqui Fellowship (to B. J. G.) from the University of Sydney. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 61-2-4734-3277; Fax: 61-2-4734-3432; E-mail: wileyj{at}medicine.usyd.edu.au.

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