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Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a
severe primary immunodeficiency disorder and systemic lupus erythematosus
#MMPMID29114388
Ameratunga R
; Koopmans W
; Woon ST
; Leung E
; Lehnert K
; Slade CA
; Tempany JC
; Enders A
; Steele R
; Browett P
; Hodgkin PD
; Bryant VL
Clin Transl Immunology
2017[Oct]; 6
(10
): e159
PMID29114388
show ga
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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