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.
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Acknowledgements
We thank the affected individuals and their families for participation in the study and H. Jabara, J. Manis, H. Oettgen, N. Ramesh and L. Kunkel for discussions. This work was supported by grants from the US Public Health Service, the Jeffrey Modell Foundation, the New England Primary Immunodeficiency Network, the March of Dimes and the Wallace Fund.
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Supplementary information
Supplementary Fig. 1
Sequence analysis of the TACI gene in index CVID and IgAD patients. (PDF 1246 kb)
Supplementary Table 1
Percentage of circulating lymphocytes. (PDF 31 kb)
Supplementary Table 2
Primer used to amplify the 5 exons of TACI gene and TACI cDNA. (PDF 39 kb)
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Castigli, E., Wilson, S., Garibyan, L. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 37, 829–834 (2005). https://doi.org/10.1038/ng1601
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DOI: https://doi.org/10.1038/ng1601
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