{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:18:29Z","timestamp":1791274709769,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2013,7,26]],"date-time":"2013-07-26T00:00:00Z","timestamp":1374796800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100006451","name":"Hospices Civils de Lyon","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006451","id-type":"DOI","asserted-by":"crossref"}]},{"name":"R\u00e9seaux Th\u00e9matiques de Recherche Translationelle INSERM"},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]},{"name":"R\u00e9gion Rhone-Alpes"},{"name":"Soci\u00e9t\u00e9 Fran\u00e7aise de Rhumatologie"},{"DOI":"10.13039\/501100001677","name":"INSERM","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011074","name":"Universit\u00e9 de Lyon","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100011074","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH","award":["RC2-AR-058959"],"award-info":[{"award-number":["RC2-AR-058959"]}]},{"name":"NIH","award":["R01-AI-063274"],"award-info":[{"award-number":["R01-AI-063274"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C5759\/A12328"],"award-info":[{"award-number":["C5759\/A12328"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100011102","name":"European Union Seventh Framework Programme","doi-asserted-by":"crossref","award":["FP7\/2007-2013 project NIMBL; 241779"],"award-info":[{"award-number":["FP7\/2007-2013 project NIMBL; 241779"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal\u2010recessive form of SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied 3 siblings with juvenile\u2010onset SLE from 1 consanguineous kindred and used next\u2010generation sequencing to identify mutations in the disease\u2010associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a homozygous missense mutation in <jats:italic>PRKCD<\/jats:italic>, encoding protein kinase \u03b4 (PKC\u03b4), in all 3 affected siblings. Mutation of <jats:italic>PRKCD<\/jats:italic> resulted in reduced expression and activity of the encoded protein PKC\u03b4 (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor\u2013 and calcium\u2010dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKC\u03b4, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that PKC\u03b4 is crucial in regulating B cell tolerance and preventing self\u2010reactivity in humans, and that PKC\u03b4 deficiency represents a novel genetic defect of apoptosis leading to SLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38008","type":"journal-article","created":{"date-parts":[[2013,5,10]],"date-time":"2013-05-10T20:10:44Z","timestamp":1368216644000},"page":"2161-2171","source":"Crossref","is-referenced-by-count":205,"title":["Protein Kinase C\u03b4 Deficiency Causes Mendelian Systemic Lupus Erythematosus With B Cell\u2010Defective Apoptosis and Hyperproliferation"],"prefix":"10.1002","volume":"65","author":[{"given":"Alexandre","family":"Belot","sequence":"first","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies R\u00e9nales Rares, Hospices Civils de Lyon, INSERM U1111, UMS3444\/US8, Universit\u00e9 Claude Bernard Lyon 1, and Universit\u00e9 de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Kasher","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor W.","family":"Trotter","sequence":"additional","affiliation":[{"name":"Paterson Institute for Cancer Research and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Perrine","family":"Foray","sequence":"additional","affiliation":[{"name":"Hospices Civils de Lyon, INSERM U1111, UMS3444\/US8, Universit\u00e9 Claude Bernard Lyon 1, and Universit\u00e9 de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Laure","family":"Debaud","sequence":"additional","affiliation":[{"name":"INSERM U1111, UMS3444\/US8, Universit\u00e9 Claude Bernard Lyon 1, and Universit\u00e9 de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian I.","family":"Rice","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Szynkiewicz","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Therese","family":"Zabot","sequence":"additional","affiliation":[{"name":"Centre de Biotechnologie Cellulaire, Groupement Hospitalier Est, and Hospices Civils de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Rouvet","sequence":"additional","affiliation":[{"name":"Centre de Biotechnologie Cellulaire, Groupement Hospitalier Est, and Hospices Civils de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev S.","family":"Bhaskar","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah B.","family":"Daly","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Mayer","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"O'Sullivan","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Juillard","sequence":"additional","affiliation":[{"name":"H\u00f4pital E. 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