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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.
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Submitted February 26, 2008
Accepted September 11, 2008
Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes
Ulrich Salzer, Chiara Bacchelli, Sylvie Buckridge, Qiang Pan-Hammarstrom, Stephanie Jennings, Vassilis 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 Anover-Sombke, Hans D Ochs, Simon Urschel, Bernd H Belohradsky, Sanja Ugrinovic, Dinakantha S Kumararatne, Tatiana C Lawrence, Are M Holm, Jose L Franco, Ilka Schulze, Pascal Schneider, E. Michael Gertz, Alejandro A. Schaffer, Lennart Hammarstrom, Adrian J Thrasher, H Bobby Gaspar, and Bodo Grimbacher*
Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany
Molecular Immunology Unit, Institute of Child Health, London, United Kingdom
Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
Clinica Pediatrica, Universita di Brescia and Istituto Medicina Molecolare "Angelo Nocivelli", Brescia, Italy
Department of Immunology and Molecular Pathology, Royal Free Hospital & University College London, London, United Kingdom
Allergy, Asthma and Immunology Clinic, Irving, TX, United States
Nuffield Department of Medicine, Oxford Radcliffe Hospital, Oxford, United Kingdom
Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
Children's Hospital and Regional Medical Center, University of Washington, Seattle, WA, United States
University Childrens Hospital, Division of Infectious Diseases and Immunology, University of Munich, Munich, Germany
Department of Clinical Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom
Department of Pediatrics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
Research Institute for Internal Medicine, National Hospital, Oslo, Norway
Grupo de Immunodeficiencias Primarias, Universidad de Antioquia, Medellin, Colombia
Department of Paediatric Pneumology and Immunology, Charite' -Humboldt University, Berlin, Germany
Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
National Center for Biotechnology Information, NIH, DHHS, Bethesda, MD, United States
* Corresponding author; email: bgrimbac{at}medsch.ucl.ac.uk.
TNFRSF13B encodes TACI, a B-cell specific 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, immunological, and clinical condition in a cohort of 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. The mutational spectrum includes 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 healthy controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed a loss of APRIL binding. However, the majority (n=41; 82%) of the 50 TACI-deficient patients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P = 1e-05, relative risk 3.6). Heterozygosity for the most common mutation C104R was associated with disease (P = 8e-04, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD-CD27+ B cells (P = .019), benign lymphoproliferation (P = 1e-05), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for CVID and influences the clinical presentation.
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