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Blood, 26 February 2009, Vol. 113, No. 9, pp. 1967-1976. Prepublished online as a Blood First Edition Paper on November 3, 2008; DOI 10.1182/blood-2008-02-141937.
IMMUNOBIOLOGY Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes1 Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany; 2 Molecular Immunology Unit, Institute of Child Health, London, United Kingdom; 3 Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; 4 Clinica Pediatrica, Università di Brescia and Istituto Medicina Molecolare "Angelo Nocivelli", Spedali Civili, Brescia, Italy; 5 Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom; 6 Allergy, Asthma, and Immunology Clinic, Irving, TX; 7 Nuffield Department of Medicine, Oxford Radcliffe Hospital, Oxford, United Kingdom; 8 Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; 9 Children's Hospital and Regional Medical Center, University of Washington, Seattle; 10 University Childrens Hospital, Division of Infectious Diseases and Immunology, University of Munich, Munich, Germany; 11 Department of Clinical Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom; 12 Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil; 13 Research Institute for Internal Medicine, National Hospital, Oslo, Norway; 14 Grupo de Immunodeficiencias Primarias, Universidad de Antioquia, Medellin, Colombia; 15 Department of Paediatric Pneumology and Immunology, Charité-Humboldt University, Berlin, Germany; 16 Department of Biochemistry, University of Lausanne, Lausanne, Switzerland; and 17 National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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.
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