TACI is mutant in common variable immunodeficiency and IgA deficiency

Abstract

The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

“…7,8 Up to the present, clinical genetics studies, which investigate on TNFRSF13B involvement in CVID, autoimmune disorders and some other diseases, are principally based on European and North American of European ancestry cases and controls, [5][6][7][8]33 with very few exceptions. 34,35 In this work, we thus describe for the first time the nucleotide diversity and the haplotype structure at the TNFRSF13B coding region in a worldwide panel of human populations.…”

“…Coding variants 204insA, C104R, A181E and C193X have been previously observed in several case-control studies. [5][6][7] Among them, 204insA, A181E and C193X resulted private patient mutations, with A181E exclusive of cases with CVID and 204insA and C193X that are also found in cases with IgAD. On the contrary, substitution C104R was present both in Italians with CVID and IgAD and in healthy Italians.…”

“…NG_007281) was amplified in five segments corresponding to the exons of the gene and their immediately intronic flanking regions, encompassing a total of 2254 bp for each individual. Amplification reactions were performed in a GeneAmp PCR System 9700 thermal cycler (Applied Biosystems, Foster City, CA, USA) as previously described, 5 except for exon 5 that required a new couple of primers (F 5 0 -CCCCGGCACAGGTTCTGGTC-3 0 and R 5 0 -TCCTCCTTTCCCTCCCTGAC-3 0 ) and a different annealing temperature (64 1C). PCR products were purified with a vacuum pump system on a Montage PCR kit (Millipore, Bedford, MA, USA) then used for sequencing reaction with ABI Prism BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems).…”

“…IgAD is even more common, with an estimated prevalence of 1:700 in the same populations; however, it is often asymptomatic and most cases remain undiagnosed. 4 After the initial claim of a strict association of TNFRSF13B mutations with both diseases, 5 the analysis of further control samples has shown the existence of some of these variants also in healthy individuals and, in familial cases, TNFRSF13B mutations do not always perfectly segregate with the pathological phenotype. 6 This has led to a reevaluation of the actual function of TNFRSF13B variants in IgAD and CVID onset, in which only the C104R and A181E mutations showed a clear correlation with the development of CVID.…”

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

“…2,3 In about 90% of patients diagnosed with agammaglobulinemia and about 75% of cases with a Hyper-IgM syndrome, the underlying genetic defect has been identified. 2 Whereas mutations have been described in patients diagnosed with CVID, [4][5][6][7][8][9][10][11][12] in over 90% of these patients no associated genetic defect has been found. In fact, in most CVID patients a complex genetic trade rather than a single affected gene is likely to contribute to development of the disease.…”