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A His-155 to Tyr Polymorphism Confers Gain-of-Function to the Human P2X₇ Receptor of Human Leukemic Lymphocytes¹

Giulio Cabrini^2,*, Simonetta Falzoni^*, Sylvia L. Forchap, Patrizia Pellegatti^*, Alessandra Balboni, Paola Agostini, Antonio Cuneo, Gianluigi Castoldi, O. Roberto Baricordi and Francesco Di Virgilio^*,

^* Section of General Pathology, Department of Experimental and Diagnostic Medicine, Department of Medical Genetics, and the Interdisciplinary Center for the Study of Inflammation; and Department of Biomedical Sciences and Advanced Therapy, Section of Hematology, University of Ferrara, Ferrara, Italy

The P2X₇R is an ATP-gated cation channel expressed in hemopoietic cells that participates in both cell proliferation and apoptosis. Expression and function of the P2X₇R have been associated with the clinical course of patients affected by chronic lymphocytic leukemia (CLL). Functional variants causing loss-of-function of the P2X₇R have been identified, namely, polymorphisms 1513A>C (E496A), 1729T>A (I568N), and 946G>A (R307Q). Here we investigated other nonsynonymous polymorphisms located either in the extracellular portion of the receptor, such as the 489C>T (H155Y) variant, or in the long cytoplasmic tail of the receptor, such as the 1068G>A (A348T), 1096C>G (T357S), and 1405A>G (Q460R) variants. P2X₇R function was monitored by measuring ATP-induced Ca²⁺ influx in PBL of patients affected by CLL and in recombinant human embryonic kidney (HEK) 293 cells stably transfected with each single P2X₇ allelic variant. Ca²⁺ influx was markedly reduced in association with the 1513C allele, whereas variants located in the same intracellular domain, such as the 1068A, 1096G, or 1405G variants, were associated with a minor functional decrease. Significant Ca²⁺ flux increase was observed in lymphocytes from CLL patients bearing the 489C/T and 489T/T genotypes in association with the 1513A/A genotype. Functional analysis in recombinant HEK293 cells expressing P2X₇R confirmed an increased ATP-dependent activation of the P2X₇ 489T mutant with respect to the wild type receptor, as assessed by both by [Ca²⁺]_i influx and ethidium uptake experiments. These data identify the 489C>T as a gain-of-function polymorphism of the P2X₇R.

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