A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 4; pp. 1222 - 1225.e10
• Main Authors: Pieper, Kathrin, PhD, Rizzi, Marta, MD, PhD, Speletas, Matthaios, MD, PhD, Smulski, Cristian R., PhD, Sic, Heiko, PhD, Kraus, Helene, MSc, Salzer, Ulrich, MD, Fiala, Gina J., MSc, Schamel, Wolfgang W., PhD, Lougaris, Vassilios, MD, Plebani, Alessandro, MD, Hammarstrom, Lennart, MD, PhD, Recher, Mike, MD, Germenis, Anastasios E., MD, PhD, Grimbacher, Bodo, MD, Warnatz, Klaus, MD, PhD, Rolink, Antonius G., PhD, Schneider, Pascal, PhD, Notarangelo, Luigi D., MD, Eibel, Hermann, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-04-2014; Elsevier; Elsevier Limited
• Subjects: Allergy and Immunology; B-Cell Activating Factor - metabolism; Biological and medical sciences; Common Variable Immunodeficiency - diagnosis; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - metabolism; Deoxyribonucleic acid; DNA; Flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Predisposition to Disease; Humans; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Ligands; Lymphocytes; Medical sciences; Medicin och hälsovetenskap; Molecular weight; Mutation; Plasmids; Polymorphism, Single Nucleotide; Protein Multimerization; Receptors, Interleukin-4 - chemistry; Receptors, Interleukin-4 - genetics; Receptors, Interleukin-4 - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Statistical analysis; Immunopathology; Common variable immunodeficiency; Immunology; Genetic variability; Immunoglobulinopathy; Genotype; Single nucleotide polymorphism; B cell activating factor receptor
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.11.021

Superimposing the structural model of BAFFR on the CRD1 of TNFR1 shows that P21 corresponds to Q46 of TNFR1 (Fig E3, B), a residue involved in TNFR1-TNFR1 interactions in the crystal structure of dimeric TNFR1 (Fig E3, C). [...]we speculated that the P21 residue might form part of the yet to be identified PLAD of BAFFR and tested whether BAFFR WT or BAFFR P21R chains self-associate like other TNFR family members. Notably, individuals heterozygous for the BAFFR deletion2 express only approximately 50% of WT BAFFR levels but have normal B-cell numbers and B-cell subsets (Fig E6, B and C). [...]a 50% reduction in BAFF binding to BAFFR per se as observed in BAFFR P21R-expressing B cells does not suffice to affect B-cell survival and subset composition.