Genetics of the P2X7 receptor and human disease

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

doi:10.1007/s11302-009-9136-4

Cited by 108 publications

(102 citation statements)

References 27 publications

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“…Three are uncommon (1-3% minor allele frequency (MAF)) but give rise to severe functional defects. 28 In particular, one of these three variants, Arg307Gln, which is located in the ATP binding pocket, dramatically alters receptor function by reducing the affinity of agonist binding. 29 Only two variants (His155Tyr and Ala348Thr) have been shown to confer gain-of-function.…”

Section: Introductionmentioning

confidence: 99%

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

et al. 2012

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The purinergic P2X7 receptor has a major role in the regulation of osteoblast and osteoclast activity and changes in receptor function may therefore affect bone mass in vivo. The aim of this study was to determine the association of non-synonymous single-nucleotide polymorphisms in the P2RX7 gene to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45-58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral fracture incidence was documented at 10 years. We found that the rate of bone loss was clearly associated with the Arg307Gln amino acid substitution such that individuals heterozygous for this polymorphism had a 40% increased rate of bone loss. Furthermore, individuals carrying the Ile568Asn variant allele had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using this model, we found a clear association between the low-risk (high-P2X7 function) alleles and low rate of bone loss. Conversely, high-risk (reduced P2X7 function) alleles were associated with a high rate of bone loss. In conclusion, an association was demonstrated between variants that reduce P2X7 receptor function and increased rate of bone loss. These data support that the P2X7 receptor is important in regulation of bone mass.

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Section: Introductionmentioning

confidence: 99%

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

et al. 2012

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“…Fourthly, mutations of rs7958311 could also alter coding of amino acids (His357 to Arg) and was associated with a partial function loss of P2X7R through affecting channel and pore function [22,23]. Rs7958311 was shown to be related with many disorders, including pulmonary tuberculosis, chronic pain, and anxiety [21,28,29]. However, the rs7958311 variant investigated in the present study was not associated with risk of OP.…”

Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

“…It is located in 12q24 and contains 13 exons spanning a 53-kb region [21]. Several single nucleotide polymorphisms (SNPs) in the P2X7R gene have been described to affect the function of this receptor, including loss of function or gain of function [21][22][23][24]. For example, three P2X7R SNPs with amino acid changes, rs3751143 (1513A > C, Glu496Ala), rs2230911 (1096 C > G, Thr357Ser), and rs7958311 (835G > A, Arg270His), were shown to lead to a loss of receptor function in both channel and pore function [22,23].…”

Section: Introductionmentioning

confidence: 99%

“…For example, three P2X7R SNPs with amino acid changes, rs3751143 (1513A > C, Glu496Ala), rs2230911 (1096 C > G, Thr357Ser), and rs7958311 (835G > A, Arg270His), were shown to lead to a loss of receptor function in both channel and pore function [22,23]. Rs3751143 and rs2230911 were reported to be associated with a higher prevalence of OP [25][26][27], while rs7958311 was shown to be related with other diseases, including pulmonary tuberculosis, chronic pain, and anxiety [21,28,29]. On the other hand, the polymorphism of rs1718119 (1068G > A, Ala348Thr) causes a gain of function of the receptor via regulating channel and pore function [30].…”

Section: Introductionmentioning

confidence: 99%

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Purinergic P2X7 receptor functional genetic polymorphisms are associated with the susceptibility to osteoporosis in Chinese postmenopausal women

Gong

et al. 2017

Purinergic Signalling

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Osteoporosis (OP) is a major public health problem worldwide. Genetic factors are considered to be major contributors to the pathogenesis of OP. The purinergic P2X7 receptor (P2X7R) has been shown to play a role in the regulation of osteoblast and osteoclast activity and has been considered as an important candidate gene for OP. A case-control study was performed to investigate the associations of functional single nucleotide polymorphisms (SNPs) in the P2X7R gene (rs2393799, rs7958311, rs1718119, rs2230911, and rs3751143) with susceptibility to OP in 400 Chinese OP patients and 400 controls. Results showed that rs3751143 was associated with OP; in particular, carriers of the C allele and CC/(AC + CC) genotypes were at a higher risk of OP, but no significant association of rs2230911, rs7958311, rs1718119, and rs2393799 with OP risk was observed. Analysis of the haplotypes revealed one haplotype (rs1718119G-rs2230911G-rs3751143C) that appeared to be a significant Brisk^haplotype with OP. The rs3751143 polymorphism was associated with osteoclast apoptosis; ATP-induced caspase-1 activity of osteoclasts with AC and CC genotypes is lower than that of osteoclasts with AA genotype in vitro. The findings suggest that the P2X7R rs3751143 functional polymorphism might contribute to OP susceptibility in Chinese postmenopausal women.

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The P2X7 Receptor

Sluyter

2017

Advances in Experimental Medicine and Biology

167

121

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The P2X7 receptor is a trimeric ion channel gated by extracellular adenosine 5'-triphosphate. The receptor is present on an increasing number of different cells types including stem, blood, glial, neural, ocular, bone, dental, exocrine, endothelial, muscle, renal and skin cells. The P2X7 receptor induces various downstream events in a cell-specific manner, including inflammatory molecule release, cell proliferation and death, metabolic events, and phagocytosis. As such this receptor plays important roles in heath and disease. Increasing knowledge about the P2X7 receptor has been gained from studies of, but not limited to, protein chemistry including cloning, site-directed mutagenesis, crystal structures and atomic modeling, as well as from studies of primary tissues and transgenic mice. This chapter focuses on the P2X7 receptor itself. This includes the P2RX7 gene and its products including splice and polymorphic variants. This chapter also reviews modulators of P2X7 receptor activation and inhibition, as well as the transcriptional regulation of the P2RX7 gene via its promoter and enhancer regions, and by microRNA and long-coding RNA. Furthermore, this chapter discusses the post-translational modification of the P2X7 receptor by N-linked glycosylation, adenosine 5'-diphosphate ribosylation and palmitoylation. Finally, this chapter reviews interaction partners of the P2X7 receptor, and its cellular localisation and trafficking within cells.

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Genetics of the P2X7 receptor and human disease

Cited by 108 publications

References 27 publications

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

Purinergic P2X7 receptor functional genetic polymorphisms are associated with the susceptibility to osteoporosis in Chinese postmenopausal women

The P2X7 Receptor

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