{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T05:38:39Z","timestamp":1793597919273,"version":"4.5.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>Membranous nephropathy (MN) results from antibodies targeting an antigen in the glomerular basement membrane (GBM). The target antigens identified so far include PLA2R, THSD7A, NELL1, SEMA3B, and EXT1\/EXT2. Using laser microdissection and mass spectrometry analysis, the authors identified a novel protein, protocadherin 7 (PCDH7), that is present in the GBM of a subset of patients with MN who are negative for all of the known antigens associated with MN. PCDH7 shows granular GBM staining and colocalizes with Ig in the GBM. Furthermore, antibodies to PCDH7 were detected in both the serum and kidney biopsy tissue from individuals with PCDH7-associated MN but not from controls. These findings suggest that PCDH7-associated MN defines a distinct type of MN.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%\u201390% of target antigens in MN.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed laser microdissection and mass spectrometry (MS\/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry\/immunofluorescence and confocal microscopy to confirm the MS\/MS finding, detect additional cases, and localize the novel protein. We also performed MS\/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MS\/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1\/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS\/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2R-negative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2020081165","type":"journal-article","created":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T12:31:25Z","timestamp":1617885085000},"page":"1249-1261","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":150,"title":["Protocadherin 7\u2013Associated Membranous Nephropathy"],"prefix":"10.1681","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-7709","authenticated-orcid":false,"given":"Sanjeev","family":"Sethi","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Madden","sequence":"additional","affiliation":[{"name":"Medical Genome Facility, Proteomics Core, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Debiec","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte de Recherche S 1155, Sorbonne Universit\u00e9, Universit\u00e9 Pierre et Marie Curie Paris 06 and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6925-1989","authenticated-orcid":false,"given":"Johann","family":"Morelle","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium"},{"name":"Institut de Recherche Exp\u00e9rimentale et Clinique, Universit\u00e9 Catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Cristine","family":"Charlesworth","sequence":"additional","affiliation":[{"name":"Medical Genome Facility, Proteomics Core, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LouAnn","family":"Gross","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Negron","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Buob","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte de Recherche S 1155, Sorbonne Universit\u00e9, Universit\u00e9 Pierre et Marie Curie Paris 06 and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Paris, France"},{"name":"Department of Pathology, Tenon Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth","family":"Chaudhry","sequence":"additional","affiliation":[{"name":"Ross University School of Medicine, Miramar, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7369-7812","authenticated-orcid":false,"given":"Michel","family":"Jadoul","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium"},{"name":"Institut de Recherche Exp\u00e9rimentale et Clinique, Universit\u00e9 Catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-209X","authenticated-orcid":false,"given":"Fernando C.","family":"Fervenza","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Ronco","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte de Recherche S 1155, Sorbonne Universit\u00e9, Universit\u00e9 Pierre et Marie Curie Paris 06 and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Paris, France"},{"name":"Division of Nephrology, Centre Hospitalier du Mans, Le Mans, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"B1-20240826","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1172\/JCI72270","article-title":"Membranous nephropathy: From models to man","volume":"124","author":"Beck","year":"2014","journal-title":"J Clin Invest"},{"key":"B2-20240826","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1016\/S0140-6736(15)60731-0","article-title":"Pathophysiological advances in membranous nephropathy: Time for a shift in patient\u2019s care","volume":"385","author":"Ronco","year":"2015","journal-title":"Lancet"},{"key":"B3-20240826","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2215\/CJN.11761116","article-title":"Primary membranous nephropathy","volume":"12","author":"Couser","year":"2017","journal-title":"Clin J Am Soc Nephrol"},{"key":"B4-20240826","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa0810457","article-title":"M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy","volume":"361","author":"Beck","year":"2009","journal-title":"N Engl J Med"},{"key":"B5-20240826","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1056\/NEJMoa1409354","article-title":"Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy","volume":"371","author":"Tomas","year":"2014","journal-title":"N Engl J Med"},{"key":"B6-20240826","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1681\/ASN.2018080852","article-title":"Exostosin 1\/exostosin 2-associated membranous nephropathy","volume":"30","author":"Sethi","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"B7-20240826","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.kint.2019.09.014","article-title":"Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy","volume":"97","author":"Sethi","year":"2020","journal-title":"Kidney Int"},{"key":"B8-20240826","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.kint.2020.05.030","article-title":"Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients","volume":"98","author":"Sethi","year":"2020","journal-title":"Kidney Int"},{"key":"B9-20240826","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1053\/j.ajkd.2020.04.013","article-title":"Podocyte antigen staining to identify distinct phenotypes and outcomes in membranous nephropathy: A retrospective multicenter cohort study","volume":"76","author":"Hanset","year":"2020","journal-title":"Am J Kidney Dis"},{"key":"B10-20240826","doi-asserted-by":"crossref","first-page":"4646","DOI":"10.1021\/ac0341261","article-title":"A statistical model for identifying proteins by tandem mass spectrometry","volume":"75","author":"Nesvizhskii","year":"2003","journal-title":"Anal Chem"},{"key":"B11-20240826","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.ekir.2020.01.018","article-title":"Proteomic analysis of complement proteins in membranous nephropathy","volume":"5","author":"Ravindran","year":"2020","journal-title":"Kidney Int Rep"},{"key":"B12-20240826","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1681\/ASN.2020071082","article-title":"New \u2018antigens\u2019 in membranous nephropathy","volume":"32","author":"Sethi","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"B13-20240826","article-title":"In patients with membranous lupus nephritis, Exostosin-positivity and Exostosin-negativity represent two different phenotypes [published online ahead of print January 21, 2021]","author":"Ravindran","journal-title":"J Am Soc Nephrol"},{"key":"B15-20240826","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.2215\/CJN.02890310","article-title":"Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain amyloidosis","volume":"5","author":"Sethi","year":"2010","journal-title":"Clin J Am Soc Nephrol"},{"key":"B16-20240826","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1097\/MNH.0b013e32835fe37c","article-title":"Mass spectrometry based proteomics in the diagnosis of kidney disease","volume":"22","author":"Sethi","year":"2013","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"B17-20240826","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1182\/blood-2009-07-230722","article-title":"Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens","volume":"114","author":"Vrana","year":"2009","journal-title":"Blood"},{"key":"B19-20240826","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1681\/ASN.2008121259","article-title":"Autoimmunity in membranous nephropathy targets aldose reductase and SOD2","volume":"21","author":"Prunotto","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"B20-20240826","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1681\/ASN.2016070776","article-title":"A proposal for a serology-based approach to membranous nephropathy","volume":"28","author":"De Vriese","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B21-20240826","doi-asserted-by":"crossref","DOI":"10.1016\/j.mayocp.2020.11.028","article-title":"A target antigen-based approach to the classification of membranous nephropathy","author":"Bobart","year":"2021","journal-title":"Mayo Clin Proc"},{"key":"B22-20240826","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.tcb.2012.03.004","article-title":"Thinking outside the cell: How cadherins drive adhesion","volume":"22","author":"Brasch","year":"2012","journal-title":"Trends Cell Biol"},{"key":"B23-20240826","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.ceb.2007.09.006","article-title":"Protocadherin family: Diversity, structure, and function","volume":"19","author":"Morishita","year":"2007","journal-title":"Curr Opin Cell Biol"},{"key":"B24-20240826","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1101\/gad.1486806","article-title":"Cadherins in development: Cell adhesion, sorting, and tissue morphogenesis","volume":"20","author":"Halbleib","year":"2006","journal-title":"Genes Dev"},{"key":"B25-20240826","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1002\/j.1460-2075.1993.tb05878.x","article-title":"Protocadherins: A large family of cadherin-related molecules in central nervous system","volume":"12","author":"Sano","year":"1993","journal-title":"EMBO J"},{"key":"B26-20240826","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/S0955-0674(02)00365-4","article-title":"Protocadherins","volume":"14","author":"Frank","year":"2002","journal-title":"Curr Opin Cell Biol"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2020081165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:30:12Z","timestamp":1786131012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2020081165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":24,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2020081165","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]},"assertion":[{"value":"2020-08-12","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-21","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}