Alternative titles; symbols
HGNC Approved Gene Symbol: PLA2R1
Cytogenetic location: 2q24.2 Genomic coordinates (GRCh38) : 2:159,923,933-160,062,615 (from NCBI)
Secretory phospholipases A2 (PLA2s) have been purified from a variety of mammalian tissues as well as from insect and snake venoms. The prototype group I PLA2, the pancreatic PLA2 (PLA2G1B; 172410), is involved in digestion, smooth muscle contraction, and cell proliferation. The prototype group II PLA2, the inflammatory-type PLA2 (PLA2G2A; 172411), is involved in inflammatory conditions and is upregulated by proinflammatory cytokines like tumor necrosis factor (TNF; 191160) and interleukin-1 (e.g., IL1B; 147720). Differential toxicity of snake venom Pla2 appears to be linked to a variety of high-affinity receptors in different organs (Ancian et al., 1995).
By screening lung and kidney cDNA libraries with a rabbit Pla2 probe, Ancian et al. (1995) isolated a cDNA encoding PLA2R1. Sequence analysis revealed that the deduced 1,465-amino acid PLA2R1 transmembrane protein contains a 25-amino acid signal sequence, 15 potential N-glycosylation sites, an N-terminal cysteine-rich domain, a fibronectin-like type II domain, 8 carbohydrate recognition domains, and a short C-terminal cytoplasmic tail containing a consensus sequence (asn-pro-X-tyr) also found in bovine Pla2r1. A casein-kinase II phosphorylation site is also located in this C-terminal region. Ancian et al. (1995) identified a splice variant encoding a soluble form of PLA2R1. Quantitative PCR analysis suggested that the ratio for the transcription of membrane to soluble PLA2R1 is 1.6. Northern blot analysis detected strong expression of 6.5- and 5.4-kb PLA2R1 transcripts in kidney, with moderate expression in placenta, lung, and skeletal muscle. Binding analysis showed that snake venom Pla2 binds to both forms of PLA2R1, and binding could be blocked by pancreatic PLA2 but not by bee venom or inflammatory PLA2. Using a radioactive probe and kinetic analyses, Ancian et al. (1995) observed that membrane PLA2R1 is internalized and that its ligand is degraded, suggesting a role for the receptor in clearing and possibly inhibiting PLA2 action.
By radioactive in situ hybridization, Ancian et al. (1995) mapped the PLA2R1 gene to 2q23-q24.
Beck et al. (2009) identified PLA2R as a target antigen in idiopathic membranous nephropathy, an organ-specific autoimmune disease. Serum samples from 26 (70%) of 37 patients with idiopathic, but not secondary, membranous nephropathy specifically identified a 185-kD glycoprotein that was present in nonreduced glomerular extract. Mass spectrometry of the reactive protein band identified the M-type phospholipase A2 receptor. Reactive serum specimens recognized recombinant PLA2R and bound the same 185-kD glomerular protein as did the monospecific antibody. Anti-PLA2R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA2R was found to be normally expressed in podocytes of human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous (SLE; 152700) or IgA nephropathy (IGAN1; 161950). The findings demonstrated that a majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA2R.
Stahl et al. (2010) reported a 56-year-old woman with biopsy-proven membranous nephropathy that progressed to end-stage renal failure necessitating renal transplantation. The nephropathy recurred within 3 days after transplantation. Anti-PLA2R antibodies were detected in serum both before and after transplantation. After rituximab therapy, the antibody titer fell from 1:100 to 1:20 and was associated with clinical improvement. Stahl et al. (2010) suggested that the presence of anti-PLA2R antibodies may identify potential risk of recurrence of membranous nephropathy in patients undergoing renal transplant.
Debiec and Ronco (2011) assessed the presence of PLA2R autoantibody in the serum and PLA2R in glomerular deposits in 42 consecutive patients with biopsy-proven membranous nephropathy (614692) without features of secondary disease. Serum samples were collected before treatment at the time of biopsy. The sensitivities of the serum and biopsy tests were 57% and 74%, respectively. Of the 42 patients, 21 with circulating PLA2R autoantibodies had PLA2R in glomerular deposits. However, Debiec and Ronco (2011) also found 3 patients who had a high circulating level of PLA2R autoantibodies at a serum dilution of 1:3000 and who did not have detectable PLA2R in glomerular deposits. The authors noted that these cases might suggest that antibodies were not nephritogenic or that epitopes were poorly accessible at the time of kidney biopsy. Eighteen patients had no detectable PLA2R autoantibodies even at a serum dilution of 1:10, although 10 of them had PLA2R in glomerular deposits. These discordant findings might be due to rapid clearance of antibodies from the blood and deposition in glomeruli or to the late referral of patients when proteinuria persisted because of irreversible ultrastructural changes. The authors concluded that the absence of circulating PLA2R autoantibody at the time of kidney biopsy does not rule out a diagnosis of PLA2R-related membranous nephropathy.
Stanescu et al. (2011) identified significant association between a SNP in PLA2R1 (rs4664308, with a p value of 8.6 x 10(-29)) and idiopathic membranous nephropathy in 3 independent populations of European descent: French, Dutch, and British.
Ancian, P., Lambeau, G., Mattei, M.-G., Lazdunski, M. The human 180-kDa receptor for secretory phospholipases A2: molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization. J. Biol. Chem. 270: 8963-8970, 1995. [PubMed: 7721806] [Full Text: https://doi.org/10.1074/jbc.270.15.8963]
Beck, L. H., Jr., Bonegio, R. G. B., Lambeau, G., Beck, D. M., Powell, D. W., Cummins, T. D., Klein, J. B., Salant, D. J. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. New Eng. J. Med. 361: 11-21, 2009. [PubMed: 19571279] [Full Text: https://doi.org/10.1056/NEJMoa0810457]
Debiec, H., Ronco, P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. (Letter) New Eng. J. Med. 364: 689-690, 2011. [PubMed: 21323563] [Full Text: https://doi.org/10.1056/NEJMc1011678]
Stahl, R., Hoxha, E., Fechner, K. PLA2R autoantibodies and recurrent membranous nephropathy after transplantation. (Letter) New Eng. J. Med. 363: 496-498, 2010. [PubMed: 20818871] [Full Text: https://doi.org/10.1056/NEJMc1003066]
Stanescu, H. C., Arcos-Burgos, M., Medlar, A., Bockenhauer, D., Kottgen, A., Dragomirescu, L., Voinescu, C., Patel, N., Pearce, K., Hubank, M., Stephens, H. A. F., Laundy, V., and 17 others. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. New Eng. J. Med. 364: 616-626, 2011. [PubMed: 21323541] [Full Text: https://doi.org/10.1056/NEJMoa1009742]