{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T01:57:14Z","timestamp":1784858234586,"version":"3.55.0"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,10,20]],"date-time":"2017-10-20T00:00:00Z","timestamp":1508457600000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin &amp;amp; Trans Imm"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non\u2010consanguineous family, who carry the C104R (c.310T&gt;C) mutation of the Transmembrane Activator Calcium\u2010modulator and cyclophilin ligand Interactor (TACI, <jats:italic>TNFRSF13B<\/jats:italic>) gene. Variants in <jats:italic>TNFRSF13B<\/jats:italic>\/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the <jats:italic>TNFRSF13B<\/jats:italic>\/TACI C104R mutation and meets the Ameratunga <jats:italic>et al.<\/jats:italic> diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the <jats:italic>TNFRSF13B<\/jats:italic>\/TACI mutation. Her brother, homozygous for the <jats:italic>TNFRSF13B<\/jats:italic>\/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole\u2010exome sequencing of the family revealed a <jats:italic>de novo<\/jats:italic> nonsense mutation (T168fsX191) in the Transcription Factor 3 (<jats:italic>TCF3<\/jats:italic>) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of <jats:italic>TNFRSF13B<\/jats:italic>\/TACI impair immunoglobulin isotype switching and antibody production predominantly via T\u2010cell\u2010independent signalling, while mutations of <jats:italic>TCF3<\/jats:italic> impair both T\u2010cell\u2010dependent and \u2010independent pathways of B\u2010cell activation and differentiation. We conclude that epistatic interactions between mutations of the <jats:italic>TNFRSF13B<\/jats:italic>\/TACI and <jats:italic>TCF3<\/jats:italic> signalling networks lead to the severe CVID\u2010like disorder and SLE in the proband.<\/jats:p>","DOI":"10.1038\/cti.2017.41","type":"journal-article","created":{"date-parts":[[2017,10,20]],"date-time":"2017-10-20T13:21:15Z","timestamp":1508505675000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Epistatic interactions between mutations of TACI (<i>TNFRSF13B<\/i>) and <i>TCF3<\/i> result in a severe primary immunodeficiency disorder and systemic lupus erythematosus"],"prefix":"10.1002","volume":"6","author":[{"given":"Rohan","family":"Ameratunga","sequence":"first","affiliation":[{"name":"Department of Virology and Immunology, Auckland City Hospital  Auckland New Zealand"},{"name":"Department of Clinical Immunology, Auckland City Hospital  Auckland New 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