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dc.contributor.authorAmeratunga, R
dc.contributor.authorKoopmans, W
dc.contributor.authorWoon, S-T
dc.contributor.authorLeung, E
dc.contributor.authorLehnert, K
dc.contributor.authorSlade, CA
dc.contributor.authorTempany, JC
dc.contributor.authorEnders, A
dc.contributor.authorSteele, R
dc.contributor.authorBrowett, P
dc.contributor.authorHodgkin, PD
dc.contributor.authorBryant, VL
dc.date.accessioned2020-12-21T04:22:59Z
dc.date.available2020-12-21T04:22:59Z
dc.date.issued2017-10-20
dc.identifier.citationAmeratunga, R., Koopmans, W., Woon, S. -T., Leung, E., Lehnert, K., Slade, C. A., Tempany, J. C., Enders, A., Steele, R., Browett, P., Hodgkin, P. D. & Bryant, V. L. (2017). Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus. CLINICAL & TRANSLATIONAL IMMUNOLOGY, 6 (10), https://doi.org/10.1038/cti.2017.41.
dc.identifier.issn2050-0068
dc.identifier.urihttp://hdl.handle.net/11343/257600
dc.description.abstractCommon 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-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/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 TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. 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 TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/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-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.
dc.languageEnglish
dc.publisherWILEY
dc.titleEpistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus
dc.typeJournal Article
dc.identifier.doi10.1038/cti.2017.41
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentMedicine Dentistry & Health Sciences
melbourne.source.titleClinical and Translational Immunology
melbourne.source.volume6
melbourne.source.issue10
dc.rights.licenseCC BY
melbourne.elementsid1278607
melbourne.contributor.authorHodgkin, Philip
melbourne.contributor.authorBryant, Vanessa
melbourne.contributor.authorSlade, Charlotte
melbourne.contributor.authorTempany, Jessica Catherine
dc.identifier.eissn2050-0068
melbourne.accessrightsOpen Access


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