Novel mutations in TNFRSF13B in pediatric patients with common variable immunodeficiency

ALMEJÚN MARÍA BELÉN; SAJAROFF ELISA; OLEASTRO MATÍAS; GALICCHIO MIGUEL; BERNASCONI ANDREA; OPPEZZO PABLO; DANIELIAN SILVIA

Buenos Aires

Congreso; First French-Argentine Immunology Congress; 2010

French Society of Immunology - Sociedad Argentina de Inmunología

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. The clinical course of CVID is complicated by systemic immunopathology including gastrointestinal, lymphoproliferative, autoimmune, and granulomatous diseases. Mutations in the gene encoding TACI (Transmembrane Activator and Calcium modulator and cyclophilin ligand Interactor, TNFRSF13B) were previously found to be associated with CVID. The aim of the present study was to determine the prevalence of TNFRSF13B mutations in Argentinean patients with pediatric presentation of CVID. We sequenced TNFRSF13B gene in a cohort of 32 Argentinean CVID patients with pediatric presentation of the disease. In patients with novel mutation we study the mRNA and protein expression of TACI by direct sequencing of cDNA or flow cytometry analysis, respectively. Among the 32 studied patients we identified 2 patients carrying a different heterozygous mutation in TNFRSF13B each other. These mutations were not found when studying 80 control chromosomes. One of them, S231R, affected the TACI highly conserved (THC) domain, important for the induction of class switch recombination (CSR). The other novel defect, S144L, is a missense mutation affecting a site previously reported in a CVID patient as a null mutation. We also evaluated the effect of these novel mutations in CSR induction. All patients from our cohort presented TACI variants (T27T, P97P, V220A, P251L, and S277S), not associated with development of CVID in previous reports, at frequencies comparable to those in either our control population and in NCBI build 36.3. In addition, C104R mutation, previously described as the most frequent in CVID, was not found in our patients. The identification of TNFRSF13B mutations, besides aiding in CVID diagnosis, could contribute to understand the mechanism that underlies CSR signaling by TACI.