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Title: Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes
Authors: Salzer, Ulrich
Bacchelli, Chiara
Buckridge, Sylvie
Pan-Hammarstrom, 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. [UNIFESP]
Holm, Are M.
Franco, Jose L.
Schulze, Ilka
Schneider, Pascal
Gertz, E. Michael
Schaffer, Alejandro A.
Hammarstrom, Lennart
Thrasher, Adrian J.
Gaspar, H. Bobby
Grimbacher, Bodo
Univ Hosp Freiburg
Inst Child Hlth
Karolinska Univ Hosp Huddinge
Univ Brescia
Spedali Civil Brescia
Royal Free Hosp
Allergy Asthma & Immunol Clin
Oxford Radcliffe Hosp
Royal Victoria Infirm
Univ Washington
Childrens Hosp
Univ Munich
Addenbrookes Hosp
Universidade Federal de São Paulo (UNIFESP)
Univ Oslo
Univ Antioquia
Charite Humboldt Univ
Univ Lausanne
Natl Lib Med
Issue Date: 26-Feb-2009
Publisher: Amer Soc Hematology
Citation: Blood. Washington: Amer Soc Hematology, v. 113, n. 9, p. 1967-1976, 2009.
Abstract: 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 patients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P < .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation. (Blood. 2009; 113: 1967-1976)
ISSN: 0006-4971
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