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Abstract: SA-PO338

Exostosin 1/Exostosin 2-Associated Membranous Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation


  • Sethi, Sanjeev, Mayo Clinic, Rochester, Minnesota, United States
  • Madden, Benjamin J., Mayo Clinic, Rochester, Minnesota, United States
  • Charlesworth, Cristine, Mayo Clinic, Rochester, Minnesota, United States
  • Fervenza, Fernando C., Mayo Clinic, Rochester, Minnesota, United States

Membranous nephropathy (MN) is is characterized by deposition of immune-complexes and complement along the glomerular basement membrane (GBM). Phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain containing 7A are target antigens in ~70% and 5% cases, respectively. In the remaining cases, the target antigen is unknown.


We studied 22 cases of MN: 7 PLA2R-positive and 15 PLA2R-negative; and 6 control time 0 transplant protocol biopsies. Glomeruli were laser microdissected and mass spectrometry (MS) was performed to detect the proteomic profile. This was followed by immunohistochemical studies (IHC) to identify and localize the overexpressed proteins.


MS identified high total spectral counts (TSC) for PLA2R in cases of PLA2R-positive MN. In 5 of the 15 PLA2R-negative MN, high TSC for both exostosin 1 (EXT1) and exostosin 2 (EXT2) were present. The TSC of EXT1 and EXT2 were comparable to the TSC of PLA2R in PLA2R-positive cases. EXT I and II are glycosyltransferases that exist as heterodimers and are responsible for the synthesis of the heparin sulfate backbone in the GBM. Of the remaining 10 PLA2R-negative cases, 2 cases of negative PLA2R by IF were positive for PLA2R, 3 cases had suboptimal tissue, and in 5 cases comparable high TSC of a single protein was not present. EXT1 and EXT2 were absent in PLA2R-positive and control cases. None of the PLA2R negative cases showed THS7DA. In all MN cases, high TSC for complement factors and Ig were also present. To confirm the findings we performed IHC that showed bright granular EXT1 and EXT2 GBM staining in EXT1/EXT2-positive MN cases, in a distribution similar to Ig (Figure 1). Furthermore, EXT1/EXT2 staining was specfic as staining for Exostosin-like 2 (EXTL2) was negative in the EXT1/EXT2-positive cases. All control and PLA2R-positive cases were negative for EXT1/EXT2/EXTL2.


A subset of PLA2R-negative MN is associated with accumulation of EXT1 and EXT2 in GBM, representing a distinct subtype of MN.

EXT1 and EXT2 staining in 3 cases of PLA2R-negative MN. Each column is 1 case.