Netrin G1 is a Novel Target Antigen in Primary Membranous Nephropathy

Linda Reinhard, Maya Machalitza, Thorsten Wiech, Hermann Josef Gröne, Moritz Lassé, Markus M. Rinschen, Nicoletta Ferru, Jan Hinrich Bräsen, Friederike Drömann, Peter Maria Rob, Sanjeev Sethi, Elion Hoxha, Rolf A.K. Stahl

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Primary membranous nephropathy (MN) is caused by circulating autoantibodies (ab) binding to antigens on the podocyte surface. PLA2R1 is the main target antigen in 70-80% of cases, but the pathogenesis is unresolved in 10-15% of patients. Methods: We used native Western blotting to identify IgG4-ab in the serum of the index MN patient, which binds an antigen endogenously expressed on podocyte membranes. These IgG4-ab were used to immunoprecipitate the target antigen and mass spectrometry used to identify Netrin G1 (NTNG1). Native Western blot and ELISA analyzed NTNG1-ab in cohorts of 888 patients with MN or other glomerular diseases. Results: NTNG1 was identified as a novel target antigen in MN. It is a membrane protein expressed in healthy podocytes. Immunohistochemistry confirmed granular NTNG1 in subepithelial glomerular immune deposits. In prospective and retrospective MN cohorts, we identified three patients with NTNG1-associated MN, who showed IgG4-dominant circulating NTNG1-ab, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1-ab were identified in 561 PLA2R1-ab positive patients, 27 THSD7A-ab positive patients, and 77 patients with other glomerular diseases. In two patients with available followup of 2 and 4 years, both NTNG1-ab and proteinuria persisted. Conclusions: NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1-ab remains to be defined.

Original languageEnglish (US)
Pages (from-to)1823-1831
Number of pages9
JournalJournal of the American Society of Nephrology
Volume33
Issue number10
DOIs
StatePublished - Oct 2022

Keywords

  • membranous nephropathy
  • Netrins
  • NTNG1-antibody

ASJC Scopus subject areas

  • Nephrology

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