Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes

• Published in: Blood 2009-02, Vol.113 (9), p.1967-1976
• Main Authors: Salzer, Ulrich, Bacchelli, Chiara, Buckridge, Sylvie, Pan-Hammarström, Qiang, Jennings, Stephanie, Lougaris, Vassilis, Bergbreiter, Astrid, Hagena, Tina, Birmelin, Jennifer, Plebani, Alessandro, Webster, A. David B., Peter, Hans-Hartmut, Suez, Daniel, Chapel, Helen, McLean-Tooke, Andrew, Spickett, Gavin P., Anover-Sombke, Stephanie, Ochs, Hans D., Urschel, Simon, Belohradsky, Bernd H., Ugrinovic, Sanja, Kumararatne, Dinakantha S., Lawrence, Tatiana C., Holm, Are M., Franco, Jose L., Schulze, Ilka, Schneider, Pascal, Gertz, E. Michael, Schäffer, Alejandro A., Hammarström, Lennart, Thrasher, Adrian J., Gaspar, H. Bobby, Grimbacher, Bodo
• Format: Article
• Language: English
• Subjects: Agammaglobulinemia - genetics; Alleles; Amino Acid Substitution; Biological and medical sciences; Case-Control Studies; Cells, Cultured; Cohort Studies; DNA Mutational Analysis; Gene Frequency; Genetic Predisposition to Disease - genetics; Hematologic and hematopoietic diseases; Heterozygote; Homozygote; Humans; Immunobiology; Medical sciences; Medicin och hälsovetenskap; Mutation - physiology; Pedigree; Polymorphism, Single Nucleotide - physiology; Risk Factors; Syndrome; Transmembrane Activator and CAML Interactor Protein - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2008-02-141937

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell– specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P