Portal de Periódicos da CAPES

Artigo Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

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

2008; Elsevier BV; Volume: 113; Issue: 9 Linguagem: Inglês

10.1182/blood-2008-02-141937

1528-0020

Ulrich Salzer, Chiara Bacchelli, Sylvie Buckridge, Qiang Pan‐Hammarström, Stephanie Jennings, V Lougaris, Astrid Bergbreiter, Tina Hagena, Jennifer Birmelin, Alessandro Plebani, A. David B. Webster, Hans-Hartmut Peter, Daniel Suez, Helen Chapel, Andrew McLean‐Tooke, Gavin P Spickett, Stephanie Añover-Sombke, Hans D. Ochs, Simon Urschel, Bernd H. Belohradsky, Sanja Ugrinović, Dinakantha Kumararatne, Tatiana Lawrence, Are Martin Holm, José Luis Franco, Ilka Schulze, Pascal Schneider, E. Michael Gertz, Alejandro A. Schäffer, Lennart Hammarström, Adrian J. Thrasher, H. Bobby Gaspar, Bodo Grimbacher,

Platelet Disorders and Treatments

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 pa-tients 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.