Novel Heterozygous Mutation 572insa In Taci Identified In A Patient With Selective Iga Deficiency

Abstract Selective IgA deficiency (SIgAD) is relatively common disease in patients with primary immunodeficiency. Recently, mutations in TNFRSF13B, encoding transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), have been identified in 7~15% of patients with common variable immunodeficiency (CVID) and 10% of those with SIgAD. However, the role of TACI mutations in the molecular pathogenesis underlying SIgAD is still controversial and remains unsolved. We identified a novel heterozygous single adenine insertion, 572insA, in exon 4 of TNFRSF13B in a patient with SIgAD. Although the same mutation was detected in her mother and younger brother, their serum immunoglobulin levels were within normal range. This frameshift mutation produces a truncated form of TACI protein lacking majority of the intracellular domain. Peripheral blood B cells from the patient and her siblings with the TACI mutation were able to produce immunoglobulin without inferiority in the presence of dendritic cells, CD40L and IL-10. However, IgD+ or IgM+ B cells from the patient were impaired to produce Cα mature transcripts in response to APRIL, one of the ligands for TACI, reflecting impairment of class-switch recombination required for differentiation into IgA-producing cells. Thus, the T-cell independent B cell activation is impaired in the patient. We overexpressed cDNAs for wild-type (WT), C104R and 572insA mutant TACI in HEK 293 cells, and analyzed the effect on signal transduction through TACI. Immuno-precipitation analysis revealed that either 572insA or C104R mutant associated with WT TACI and formed an oligomeric complex. C104R TACI has been previously shown to exert a dominant-negative effect on ligand-induced TACI signaling, since it forms an oligomeric complex with WT TACI and disrupts ligand-induced receptor signaling. Similarly, since 572insA TACI lacks an intracellular domain that is important for signal transduction, it may exert a dominant-negative effect on ligand-induced TACI signaling. Although the heterozygous 572insA TACI mutation disrupts ligand-induced TACI signaling, not all individuals carrying the mutation display humoral immune deficiency. Thus, an additional genetic modifier and/or an environmental factor may be required for the development of immunological abnormalities due to TACI mutations.