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Phospholipase A2 Receptor ( PLA2R1 ) Sequence Variants in Idiopathic Membranous Nephropathy

Marieke J.H. Coenen 1, * Julia Hofstra 2 Hanna Debiec 3, 4 Horia Stanescu 5 Alan Medlar 5 Bénédicte Stengel 6 Anne Boland-Augé 7 Johanne Groothuismink 1 Detlef Bockenhauer 5 Steve Powis 5 Peter Mathieson 8 Paul Brenchley 9 Robert Kleta 5 Jack F.M. Wetzels 2 Pierre Ronco 3, 4, *
* Corresponding author
1 Department of Human Genetics [Nijmegen]
2 Department of Nephrology [Nijmegen, The Netherlands]
3 Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation
4 Service de Néphrologie et Dialyses [CHU Tenon]
5 Centre for Nephrology [London, UK]
6 CESP - Centre de recherche en épidémiologie et santé des populations
7 CNG - Centre National de Génotypage
8 Academic Renal Unit [Bristol, UK]
9 School of Biomedicine [Manchester, UK]
Abstract : The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.
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Marieke J.H. Coenen, Julia Hofstra, Hanna Debiec, Horia Stanescu, Alan Medlar, et al.. Phospholipase A2 Receptor ( PLA2R1 ) Sequence Variants in Idiopathic Membranous Nephropathy. Journal of the American Society of Nephrology, American Society of Nephrology, 2013, 24 (4), pp.677-683. ⟨10.1681/ASN.2012070730⟩. ⟨inserm-02191539⟩

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