Browsing by Author "Baran, Alperen"

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    A novel heterozygous NFKB2 variant in a multiplex family with common variable immune deficiency and autoantibodies against type I IFNs
    (Springer New York LLC, 2024-11-23) Baran, Alperen; Lülecioğlu, Aysima Atılgan; Gao, Liwei; Yazıcı, Yılmaz Yücehan; Demirel, Fevzi; Metin, Ayşe; Casanova, Jean-Laurent; Pue, Anne; Le Voyer, Tom; Beyaz, Şengül; Belkaya, Serkan
    We studied a family with three male individuals across two generations affected by common variable immune deficiency (CVID). We identified a novel missense heterozygous variant (c.2602T>A:p.Y868N) of NFKB2 in all patients and not in healthy relatives. Functional studies of the mutant allele in an overexpression system and of the patients’ cells confirmed the deleteriousness of the NFKB2 variant and genotype, respectively, on the activation of the non-canonical NF-κB signaling pathway. Impaired processing of p100 into p52 underlies p100 accumulation, which results in gain-of-function (GOF) of IκBδ inhibitory activity and loss-of-function (LOF) of p52 transcriptional activity. The three patients’ plasma contained autoantibodies that neutralized IFN-α2 and/or IFN-ω, accounting for the severe or recurrent viral diseases of the patients, including influenza pneumonia in one sibling, and severe COVID-19 and recurrent herpes labialis in another. Our results confirm that NFKB2 alleles that are IκBδ GOF and p52 LOF can underlie CVID and drive the production of autoantibodies neutralizing type I IFNs, thereby predisposing to severe viral diseases.
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    Ahmet Urkay ve Halıcı Ahmet Urkay Müzesi
    (Bilkent University, 2020) Akpınar, Ahmet Enes; Baran, Alperen; Altay, Burcu; Güneri, Furkan; İnce, Osman Batur
    Bu çalışmamızda öncelikle Türkiye'de müzeciliğin ortaya çıkışı, Osmanlı ve Cumhuriyet devirlerindeki gelişim süreci ve nispeten son yıllarda ortaya çıkan özel müzecilik kavramını ortaya çıkaran hukuki süreç aktarılmıştır. Daha sonra ise bu özel müzelerden birisi olan Ahmet Urkay Müzesi üzerinde durulmuştur. Müzenin kurucusu Ahmet Urkay'ın kısaca biyografisi ve müzede sergilediği eserleri nasıl ve nerelerden edindiği, müzesini ilk olarak Marmaris'te kurmasının nedeni ve sonuçları, müzenin daha sonra Denizli-Karahayıt'a taşımasının sebepleri ve sonuçları ve bu müzenin her iki bölgenin kültürünü nasıl etkilediği incelenmiştir.
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    Characterization of a novel heterozygous NFKB2 variant in a multiplex family with common variable immune deficiency
    (2024-08) Baran, Alperen
    Common variable immune deficiency (CVID) is a complex primary immunodeficiency characterized by low levels of serum immunoglobulins (IgG, and IgA and/or IgM) and higher vulnerability to recurrent infections, autoimmunity, and malignancies. Despite extensive clinical characterization, the underlying genetic causes of CVID remain elusive in many cases, complicating both diagnosis and treatment. In our study, we conducted a detailed genetic investigation of a multiplex family, in which both father and his two sons were affected by CVID. To identify inborn monogenic defects underlying CVID in this family, we performed whole exome sequencing (WES) on two affected members. We discovered a novel missense heterozygous variant (NM_001322934.2:c.2602T>A:p.Y868N) in NFKB2, encoding NF-κB2 protein, present in all patients but absent in the healthy mother, consistent with an autosomal dominant mode of inheritance with complete penetrance. To characterize the impact of this variant on the expression and function NF-κB2, we conducted various biochemical and functional studies using overexpression systems and patients’ cells. We showed that the p.Y868N variant impairs the generation of active p52 from p100, thereby culminating in p100 accumulation. This accumulation leads to a gain-of-function (GOF) in inhibitory activity of IκBδ and a loss-of-function (LOF) in transcriptional activity of p52. These results suggested a causative link between the NFKB2 mutation and CVID in the patients. Our findings further expand the genetic spectrum of CVID and emphasize the importance of incorporating next generation sequencing technologies, such as WES, in the diagnostic evaluation of patients with CVID. Genetic dissection of CVID not only enhances our current understanding of its pathogenesis in humans, but also provides genetic testing and counselling in affected families and supports the development of more personalized therapeutic approaches, ultimately improving disease outcomes.
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    Whole-exome sequencing for genetic diagnosis of idiopathic liver injury in children
    (Wiley-Blackwell Publishing Ltd., 2024-06) Lülecioğlu, Ayşima Atılgan; Yazıcı, Yılmaz Yücehan; Baran, Alperen; Warasnhe, Khaled; Beyaz, Şengül; Aytekin, Caner; Özcay, Figen; Aydemir, Yusuf; Barış, Zeren; Belkaya, Serkan
    Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.