TACI is mutant in common variable immunodeficiency and IgA deficiency

• Published in: Nature genetics Vol. 37; no. 8; pp. 829 - 834
• Main Authors: Castigli, Emanuela, Wilson, Stephen A, Garibyan, Lilit, Rachid, Rima, Bonilla, Francisco, Schneider, Lynda, Geha, Raif S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2005; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; B-Lymphocytes - metabolism; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Calcium; Cancer Research; Common Variable Immunodeficiency - genetics; Complications and side effects; Diagnosis; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Humans; IgA Deficiency - genetics; Immunoglobulins - metabolism; Immunological deficiency syndromes; Ligands; Membrane Proteins - blood; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mutation; Mutation, Missense; Phenotype; Receptors, Tumor Necrosis Factor - blood; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Risk factors; Transmembrane Activator and CAML Interactor Protein; United States; IgA; Common variable immunodeficiency; Mutation; Deficiency
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1601

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.