In a mother and son with common variable immunodeficiency-2 (240500), Castigli et al. (2005) identified a heterozygous 310T-C transition in exon 3 of the TNFRSF13B gene that resulted in a cys104-to-arg (C104R) substitution in the extracellular domain of TACI. Another unrelated woman with CVID2 was compound heterozygous for C104R and a single-basepair insertion (604907.0004). She inherited the C104R mutation from her father, who had selective immunoglobulin A deficiency-2 (609529), and transmitted the heterozygous C104R mutation to her son, who had CVID2. The proband's 2 sisters, who had IGAD2, were also heterozygous for the mutation. Heterozygosity for C104R was also found in 4 members of a third family with IGAD2. Studies of patient B cells showed that the mutant protein was expressed on the surface, but was unable to bind the ligand BAFF (603969); stimulation with APRIL (604472) failed to stimulate IgA or IgG secretion from B cells.
Salzer et al. (2005) identified the C104R mutation in affected members of a family with multiple cases of humoral immunodeficiency; 3 individuals who were heterozygous for the mutation had IGAD2, whereas 1 individuals who was homozygous for the mutation had CVID2. In addition, 2 unrelated patients with sporadic CVID were heterozygous for the mutation. Transformed B lymphocytes from patients showed severely compromised binding to APRIL and compromised B-cell proliferation; APRIL and BAFF failed to induce class-switch recombination in TACI-deficient B cells. Salzer et al. (2005) referred to the nucleotide substitution as 323T-C. The authors suggested that the incomplete penetrance of TACI mutations may reflect partial redundancy of the system.
Using in vitro transfection assays, Garibyan et al. (2007) showed that the C104R mutation, as well as its murine counterpart (C76R), interfered with TACI signaling in a dominant manner that was dependent on preassociation of C104R mutant TACI with wildtype TACI in the absence of ligand. Ligand was able to bind wildtype TACI, suggesting that C104R disrupts ligand-induced receptor rearrangement and signaling. These findings revealed that TACI preassembles as a homotypic oligomeric complex before binding ligand and provided a mechanism for how the heterozygous C104R mutation leads to CVID.
