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Journals / Sağlık Bilimlerinde İleri Araştırmalar Dergisi / 2023 / Volume: 6 Issue: 3

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

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

Sinem Fırtına(ISTANBUL UNIVERSITY-CERRAHPASA, CERRAHPAŞA SCHOOL OF MEDICINE, DEPARTMENT OF INTERNAL MEDICINE, DEPARTMENT OF MEDICAL GENETICS)0000-0002-3370-8545
Aslı Kutlu(Istinye University, Engineering and Natural Science Faculty, Department of Molecular Biology and Genetics)0000-0002-9169-388X
Begüm Işıkgil(Istinye University, Institute for Graduate Education, Department of Medical Biology and Genetics)0000-0002-7541-4596
Medinenur Yozlu(GEBZE TECHNICAL UNIVERSITY, FACULTY OF BASIC SCIENCES, DEPARTMENT OF MOLECULAR BIOLOGY AND GENETICS)0000-0002-3580-7280
Beyza Nur Çepeci(GEBZE TECHNICAL UNIVERSITY, FACULTY OF BASIC SCIENCES, DEPARTMENT OF MOLECULAR BIOLOGY AND GENETICS)0000-0001-9417-2943
Hülya Yılmaz(ISTANBUL UNIVERSITY-CERRAHPASA, CERRAHPAŞA SCHOOL OF MEDICINE, DEPARTMENT OF INTERNAL MEDICINE, DEPARTMENT OF INTERNAL MEDICINE, HEMATOLOGY)0000-0001-5664-5893
Yuk Yin Ng(ISTANBUL BILGI UNIVERSITY, FACULTY OF ENGINEERING AND NATURAL SCIENCES, DEPARTMENT OF GENETICS AND BIOENGINEERING)0000-0001-9755-6045
Özden Hatırnaz Ng(ACIBADEM MEHMET ALI AYDINLAR UNIVERSITY, SCHOOL OF MEDICINE, DEPARTMENT OF INTERNAL MEDICINE, DEPARTMENT OF MEDICAL GENETICS (MEDICINE))0000-0001-7728-6527
Ayça Kıykım(Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Infectious Diseases, Division Allergy and Clinical Immunology)0000-0001-5821-3963
Esra Yücel Özek(Istanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Division Pediatric Allergy and Immunology)0000-0003-3712-2522
Elif Karakoç Aydıner(Marmara University, Faculty of Medicine, Department of Pediatrics, Division Pediatric Allergy and Immunology)0000-0003-4150-5200
Safa Barış(Marmara University, Faculty of Medicine, Department of Pediatrics, Division Pediatric Allergy and Immunology)0000-0002-4730-9422
Ahmet Oğuzhan Özen(Marmara University, Faculty of Medicine, Department of Pediatrics, Division Pediatric Allergy and Immunology)0000-0002-9065-1901
Serdar Nepesov(Medical Park Goztepe Hospital, Clinic of Pediatrics, Division of Pediatric Allergy and Immunology)0000-0002-4551-5433
Yıldız Camcıoğlu(Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Infectious Diseases, Division Allergy and Clinical Immunology)0000-0002-4796-6828
İsmail Reisli(Necmettin Erbakan University, Faculty of Medicine, Department of Pediatrics, Division Pediatric Allergy and Immunology)0000-0001-8247-6405
Muhlis Cem Ar(ISTANBUL UNIVERSITY-CERRAHPASA, CERRAHPAŞA SCHOOL OF MEDICINE, DEPARTMENT OF INTERNAL MEDICINE, DEPARTMENT OF INTERNAL MEDICINE, HEMATOLOGY)0000-0002-0332-9253
Müge Aydın Sayitoğlu(ISTANBUL UNIVERSITY, AZIZ SANCAR INSTITUTE OF EXPERIMENTAL MEDICINE, DEPARTMENT OF GENETICS)0000-0002-8648-213X
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Publication Date
2023-10-24
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

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.

📌 3 Key Takeaways

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Objective & Hypothesis: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.
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Key Findings & Data:Impaired expression of the TNFRSF13B gene is associated with common variable immune deficiency (CVID), autoimmunity, and lymphoproliferation disorders.
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Conclusion & Impact: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.
🔬Design:Research Article
📍Scope:Comprehensive Sample
⚙️Variables:TNFRSF13B · in silico analysis · CVID

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.

Özet

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.

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Cite This Article

Fırtına, S., Kutlu, A., Işıkgil, B., Yozlu, M., Çepeci, B. N., Yılmaz, H., Ng, Y. Y., Ng, Ö. H., Kıykım, A., Özek, E. Y., Aydıner, E. K., Barış, S., Özen, A. O., Nepesov, S., Camcıoğlu, Y., Reisli, İ., Ar, M. C., Sayitoğlu, M. A. (2023). TNFRSF13B VARIANTS ACT AS MODIFIERS TO CLINICAL PHENOTYPES IN COMMON VARIABLE IMMUNE DEFICIENCY DISORDERS. Sağlık Bilimlerinde İleri Araştırmalar Dergisi, Volume: 6 Issue: 3. https://doi.org/10.26650/JARHS2023-1346155

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