TNFRSF13B VARIANTS ACT AS MODIFIERS TO CLINICAL PHENOTYPES IN COMMON VARIABLE IMMUNE DEFICIENCY DISORDERS

Abstract

Objective: The TNF receptor gene 13B (TNFSRF13B) is a member of the TNF superfamily which is crucial for B cell maturation, plasma cell differentiation, and antibody response. Impaired expression of the TNFRSF13B gene is associated with common variable immune deficiency (CVID), autoimmunity, and lymphoproliferation disorders. Besides the disease-causing variants of this gene, its different isoforms are associated with strong and weak TNFRSF13B expression that leads to an unbalanced B cell response. Materials and Methods: The study detected 26 variants (three synonymous, five missenses, eleven UTR, and seven intronic variants) in the TNFRSF13B gene by screening 68 CVID patients with targeted next generation sequencing. An integrative bioinformatics approach was utilized to provide a plausible explanation for CVID associations from different perspectives and to investigate the associations from the clinical findings. Results: Fifty-eight percent (15/26) of the detected variants were altered regulatory elements, such as transcription factor binding, miRNA binding sites, splice site regions or the thermodynamic impact on protein. We observed that patients who suffered from the potential splicing variants had significantly low IgA levels (p=0.009), autoimmunity (p=0.02) and gastrointestinal findings (p=0.05). In addition, the c.*79A>G 3-UTR variant was found with the low IgA and IgE levels. Thirteen variants found to have at least tenfold increased allele frequencies as compared to global databases indicating that the TNFRSF13B variants, which have a potential regulatory effect, are more common in CVID patients. Conclusions: All findings suggested that these variants may not be the causative variant for the CVID phenotype but the unbalanced TNFRSF13B alternative splices could contribute to the pathogenesis of patients independent from the underlying genetic background of CVID.

Keywords

• TNFRSF13B
• in silico analysis
• CVID
• integrated bioinformatics
• PID

Supporting Institution

Istanbul University Cerrahpasa Research Fund

Project Number

project no: TYO-2017-24271

Thanks

We would like to thank to Dr. Ozkan Ozdemir for his interpretation for creating a graphical figure 1 with Biorender program.

TNFRSF13B VARYANTLARI, YAYGIN DEĞİŞKEN İMMÜN YETMEZLİK KLİNİK FENOTİPİNİN DÜZENLENMESİNDE ROL OYNAR

Abstract

Amaç: TNF reseptör üst ailesi üyesi 13B (TNFSRF13B), B hücre olgunlaşması, plazma hücresi farklılaşması ve antikor yanıtı için kritik olan TNF üst ailesinin bir üyesidir. TNFRSF13B geninin bozulmuş ifadesi, yaygın değişken immün yetmezlik (YDİY), otoimmünite ve lenfoproliferasyon bozuklukları ile ilişkilendirilir. Bu genin hastalığa neden olan varyantlarının yanı sıra bazı farklı izoformlarınında B hücre yanıtını değiştirdiği gösterilmiştir. Gereç ve Yöntemler: Bu çalışmada, 68 YDİY hastası yeni nesil dizileme yöntemi ile taranarak TNFRSF13B geninde 26 varyant (üç sinonim, beş yanlış anlamlı, on bir UTR ve yedi intronik varyant) saptanmıştır. Tespit edilen varyantlar etkilerine göre biyoinformatik araçlar ile modellenmiş, etkili olduğu gösterilen varyantların klinik bulgular ile ilişkisi araştırılmıştır. Bulgular: Saptanan varyantların (15/26) %58’i, transkripsiyon faktörü ya da miRNA bağlama bölgeleri, kırpılma bölgeleri veya protein üzerinde termodinamik etkisi olabileceği gösterilen varyantlardır. Biyoinformatik olarak kırpılma bölgesini değiştirdiği düşünülen varyantlara sahip hastalarda, diğer hastalara göre anlamlı derecede düşük IgA düzeylerinin (p=0,009), otoimmünite varlığının (p=0,02) ve gastrointestinal bulgular (p=0,05) gibi YDİY fenotipinde görülen bulguların olduğunu gözlemledik. Ayrıca c.*79A>G 3-UTR varyantının düşük IgA ve IgE seviyeleri ile ilişkili olduğu bulunmuştur. Global veritabanlarına kıyasla on üç varyantın en az on kat artmış alel frekanslarına sahip olduğu bulundu. Bu fark potansiyel düzenleyici etkiye sahip TNFRSF13B varyantlarının YDİY hastalarında daha yaygın olduğunu göstermektedir. Sonuçlar: Bu bulgular, TNFRSF13B’deki varyantların YDİY fenotipini açıklamasa da, kırpılma bölgesini değiştirme potansiyeli olan varyantların YDİY’in altında yatan genetik arka plandan bağımsız olarak hastaların patogenezine katkıda bulunabileceğini göstermiştir.

Keywords

• TNFRSF13B
• in siliko analiz
• YDİY
• entegre biyoinformatik
• PİY

Project Number

project no: TYO-2017-24271

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