Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus
Web of Science
AuthorAmeratunga, R; Koopmans, W; Woon, S-T; Leung, E; Lehnert, K; Slade, CA; Tempany, JC; Enders, A; Steele, R; Browett, P; ...
Source TitleClinical & Translational Immunology
University of Melbourne Author/sHodgkin, Philip; Bryant, Vanessa; Slade, Charlotte; Tempany, Jessica Catherine
AffiliationMedical Biology (W.E.H.I.)
Medicine Dentistry & Health Sciences
Document TypeJournal Article
CitationsAmeratunga, 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.
Access StatusOpen Access
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-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.
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