Sequence Analysis of TNFRSF13b, Encoding TACI, in Patients with Systemic Lupus Erythematosus

Abstract

B cell activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL), and their receptors BAFF receptor (BAFFR), B cell maturation antigen (BCMA), and transmembrane activator and CAML interactor (TACI) are involved in the regulation of B cell homeostasis and differentiation. BAFF overexpression leads to systemic lupus erythematosus (SLE) in mice and elevated BAFF levels have been observed in human SLE and mouse models for SLE. Furthermore, genetic inactivation of TACI in mice results in a SLE-like phenotype. Based on our recent finding that TACI is mutated in patients with common variable immunodeficiency, of whom more than 30% suffer from autoimmune conditions, we analyzed TACI in humans with SLE. Sequence analysis of TNFRSF13b/TACI in 119 unrelated SLE patients revealed four variants: R20C in exon 1, R72H in exon 3, the silent variation c.327 G > A in exon 3, and A181E in exon 4. No significant association with any of these variants was found, when compared to the frequencies of the variants in a healthy control cohort. Furthermore, the mutated alleles R20C and R72H did not segregate with the SLE phenotype in familial cases of SLE. Thus, our evaluation of the coding region of TNFRSF13b/TACI did not reveal any deleterious or disease-associated mutations.

Heterozygous Alterations ofTNFRSF13B/TACIin Tonsillar Hypertrophy and Sarcoidosis

“…Indeed, our results are in favor of our hypothesis, since the mutations identified in the patients affected by TH without evidence of infectious cause are both deleterious for TACI function and extremely rare in the general population (0.1-0.2%); in addition, the frequency of TNFRSF13B/TACI mutations in TH patients (10.5%) was also higher than that expected for the general population (1.2–3.6% in several healthy control groups) [4, 12, 14]. One of the limitations of this study is that the number of patients with TH was rather small; this is partly due to the fact that TH without pathogen cause, established by conventional and molecular techniques, is rather a rare condition.…”

“…These findings have raised the question whether TNFRSF13B/TACI mutations contribute to the pathogenesis of human pathologic conditions similar to those observed in TACI-deficient mice, or diseases with clinical manifestations similar to those observed in CVID, such as sarcoidosis. Until now, only one study has analyzed the role of TNFRSF13B/TACI in systemic lupus erythematosus but did not reveal any deleterious or disease-associated mutations into the coding region of the gene [12]. However, the contribution of TNFRSF13B/TACI alterations in the pathogenesis of human lymphoproliferative disorders, malignant or benign, is elusive.…”

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

“…7,8 Up to the present, clinical genetics studies, which investigate on TNFRSF13B involvement in CVID, autoimmune disorders and some other diseases, are principally based on European and North American of European ancestry cases and controls, [5][6][7][8]33 with very few exceptions. 34,35 In this work, we thus describe for the first time the nucleotide diversity and the haplotype structure at the TNFRSF13B coding region in a worldwide panel of human populations.…”

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

“…27 Heteroduplex formation was induced by mixing equal amounts of patient polymerase chain reaction (PCR) product with a control DNA PCR product followed by denaturation at 95°C for 5 minutes with 5°C decrements every 2 minutes until the base holding temperature (25°C) was reached. Heteroduplex analysis was carried out on an ABI Prism 377 DNA Sequencer (PE Applied Biosystems, Foster City, CA) and on a MegaBACE 1000 DNA Analyser (GE Healthcare, Chalfont St Giles, United Kingdom).…”