Browsing by Author "Belkaya, Serkan"

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Open Access
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.
Open Access
A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers
(Elsevier, 2023-07-01) Yazıcı, Yılmaz Yücehan; Belkaya, Serkan; Timuçin, E.
Interleukin 18 (IL18) is a pro-inflammatory cytokine that modulates innate and adaptive immune responses. IL18 activity is tightly controlled by the constitutively secreted IL18 binding protein (IL18BP). PDB structures of human IL18 showed that a short stretch of amino acids between 68 and 81 adopted a disordered conformation in all IL18-IL18BP complexes while adopting a 310 helical structure in other IL18 structures, including the receptor complexes. The C74 of human IL18, which was reported to form a novel intermolecular disulfide bond in the human tetrameric assembly, is also located in this short epitope. These observations reflected the importance of this short surface epitope for the structure and dynamics of the IL18-IL18BP heterodimers. We have analyzed all known IL18-IL18BP complexes in the PDB by all-atom MD simulations. The analysis also included two computed complex models adopting a helical structure for the surface epitope. Heterodimer simulations showed a stabilizing impact of the small surface region at the helical form by reducing flexibility of the complex backbone. Analysis of the symmetry-related human IL18-IL18BP tetramer showed that the unfolding of this small surface region also contributed to the IL18-IL18BP stability through a completely exposed C74 sidechain to form an intermolecular disulfide bond in the self-assembled human IL18-IL18BP dimer. Our findings showed how the conformation of the short IL18 epitope between amino acids 68 and 81 would affect IL18 activity by mediating the intermolecular interactions of IL18.
Open Access
An infant with zoonotic pulmonary tuberculosis due to mycobacterium bovis
(2023-04-12) Üstündaǧ, G.; Şahin, A.; Yazıcı, Yücehan Yılmaz; Aksay, A.; Biçmen, C.; Belkaya, Serkan; Yilmaz, D.
Bovine tuberculosis might be seen in low-income countries, especially in children fed with raw milk. The most common transmission route is fecal-oral way, and it is most likely through unpasteurized dairy products. Although clinical and radiological findings are like non-zoonotic tuberculosis, treatment approaches may differ in individuals with zoonotic tuberculosis. Prevention of zoonotic diseases requires multidisciplinary approaches. These approaches include the development of veterinary and surveillance studies for the detection of communicable diseases in farm animals, as well as informing the public about raw milk consumption. In this case report, a patient with zoonotic pulmonary tuberculosis related to Mycobacterium bovis because of consumption of raw milk was presented. A five-month-old male was admitted to the hospital due to a persistent, feverless, non-productive cough since birth. Empirical antibiotic treatment was started with a preliminary diagnosis of pneumonia because of left upper lobe and right pericardial infiltration on chest X-ray. However, after two weeks of antimicrobial therapy, the patient's clinical and laboratory findings did not improve. This led to the referral for a computed tomography imaging, which revealed tracheomalacia, consolidation on the right upper lobe, an indistinguishable mass or consolidation on the left middle lobe of the lung, peribronchial thickening on the basal segment of the lower lobe, and mediastinal lymphadenopathy. Three consecutive days of fasting gastric lavage fluid was sent to the reference laboratory for acid-resistant bacillus examination, polymerase chain reaction (PCR) and culture studies. As the clinical findings were compatible and PCR was positive, the patient was started on quadruple antituberculous therapy. After initiation of anti-tuberculosis drugs, the patient's findings radiologically and clinically were improved. Mycobacterium bovis was grown in the culture. In the meantime, it was discovered that the patient was fed with raw milk. Due to the patient's clinical symptoms and the growth of Mycobacterium bovis in the gastric lavage fluid culture, the diagnosis of bovine tuberculosis was made. The culprit was that the milk of the cow belonging to the patient's family, which was later found to be infected with M.bovis, was milked and given to the patient without boiling. Today, unpasteurized dairy products continue to be consumed, especially in rural areas. One of the most important steps to prevent zoonotic diseases is to raise awareness about not consuming raw milk and undercooked meat. To elucidate the epidemiological link in childhood, taking a good anamnesis, including questioning raw milk consumption, is essential in the diagnosis of tuberculosis. © 2023 Ankara Microbiology Society. All rights reserved.
Open Access
Circulating Pentraxin-3 and its association with C-reactive protein levels and disease activity in patients with chronic spontaneous urticaria
(Codon Publications, 2023-07-01) Beyaz, Ş.; Belkaya, Serkan; Öztop, N.
Introduction: Pentraxin-3 (PTX3) is a soluble long pentraxin molecule that regulates inflammatory responses. This study aimed to determine the plasma levels of plasma PTX-3 as an inflammation marker in chronic spontaneous urticaria (CSU) and whether the PTX3 levels correlate with disease activity and other clinical parameters, including acute phase reactants and biomarkers. Methods: The study included 70 CSU patients and 30 healthy controls. Plasma PTX3 levels were measured by ELISA. CSU disease activity was evaluated with the urticaria activity score summed over 7 days. Complete blood count, C-reactive protein (CRP), transaminases, total IgE, antinuclear antibody, anti-thyroid peroxidase, anti-thyroglobulin, and D-dimer levels were recorded. Results: Of the 70 patients, 52 (74.3%) were female, with a mean age of 37.51 ± 11.80 years. Disease activity was severe in 43, moderate in 15, and mild in 12 patients. Mean PTX3 levels were elevated in CSU patients compared to healthy controls (0.81 vs. 0.55 ng/mL, p = 0.031). The mean CRP levels were higher in patients than in the controls (4.26 vs. 1.57 mg/L, p = 0.023). Patients also had higher D-dimer levels than the controls (5.96 vs. 0.59 mg/L, p < 0.001). A significant positive correlation was found between PTX3 and CRP levels (r = 0.508, p < 0.001) and between D-dimer levels and UAS7 (r = 0.338, p = 0.004) and CRP (r = 0.213, p = 0.034) levels. A multivariable stepwise regression analysis showed that the one-unit increase in the CRP level increased to 38.19 units in the PTX3 level (95% confidence interval [17.40–58.98], p < 0.001). Conclusion: Circulating levels of CRP and PTX3, two members of the pentraxin family, are significantly correlated and elevated in CSU patients with increasing disease activity, indicating their utility as inflammatory markers in CSU.
Embargo
Computational modeling of the anti-inflammatory complexes of IL37
(Elsevier Inc., 2025-01-18) Şardağ, İnci; Düvenci, Zeynep Şevval; Belkaya, Serkan; Timuçin, Emel
Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. However, none of the structures of IL37 complexes have been experimentally characterized. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations. We modeled all protein–protein complexes of IL37 using a range of methods from homology modeling to AlphaFold2 multimer predictions. Models that successfully recapitulated experimental features underwent further analysis through molecular dynamics simulations. As positive controls, binary and ternary complexes of IL18 from PDB were included for comparison. Several key findings emerged from the comparative analysis of IL37 and IL18 complexes. IL37 complexes exhibited higher mobility than the IL18 complexes. Simulations of the IL37-IL18Rα complex revealed altered receptor conformations capable of accommodating a dimeric IL37, with the N-terminal loop of IL37 contributing significantly to complex mobility. Additionally, the glycosyl chain on N297 of IL18Rα, which contours one edge of the cytokine binding surface, acted as a steric block against the N-terminal loop of IL37. Further, investigations into interactions between IL37 and IL18BP suggested that a binding mode homologous to IL18 was unstable for IL37, indicating an alternative binding mechanism. Altogether, this study accesses to the structure and dynamics of IL37 complexes, revealing the structural underpinnings of the IL37’s modulatory effect on the IL18 signaling pathway.
Open Access
Fulminant viral hepatitis in two siblings with inherited IL-10RB deficiency
(Springer, 2022-10-29) Korol, Cecilia B.; Belkaya, Serkan; Alsohime, Fahad; Lorenzo, Lazaro; Boisson-Dupuis, Stéphanie; Brancale, Joseph; Neehus, Anna-Lena; Vilarinho, Silvia; Zobaida, Alsum; Halwani, Rabih; Al-Muhsen, Saleh; Casanova, Jean-Laurent; Jouanguy, Emmanuelle
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses. © 2022, The Author(s).
Open Access
Genetic investigation of severe viral diseases in children
(Wiley-Blackwell Publishing, 2023-01) Belkaya, Serkan
Open Access
Human TMEFF1 is a restriction factor for herpes simplex virus in the brain
(NATURE PORTFOLIO, 2024-07) Chan, Yi-Hao; Liu, Zhiyong; Bastard, Paul; Khobrekar, Noopur; Hutchison, Kennen M.; Yamazaki, Yasuhiro; Fan, Qing; Matuozzo, Daniela; Harschnitz, Oliver; Kerrouche, Nacim; Nakajima, Koji; Amin, Param; Yatim, Ahmad; Rinchai, Darawan; Chen, Jie; Zhang, Peng; Ciceri, Gabriele; Chen, Jia; Dobbs, Kerry; Belkaya, Serkan; Lee, Danyel; Gervais, Adrian; Aydin, Kuersad; Kartal, Ayse; Hasek, Mary L.; Zhao, Shuxiang; Reino, Eduardo Garcia; Lee, Yoon Seung; Seeleuthner, Yoann; Chaldebas, Matthieu; Bailey, Rasheed; Vanhulle, Catherine; Lorenzo, Lazaro; Boucherit, Soraya; Rozenberg, Flore; Marr, Nico; Mogensen, Trine H.; Aubart, Melodie; Cobat, Aurelie; Dulac, Olivier; Emiroglu, Melike; Paludan, Soren R.; Abel, Laurent; Notarangelo, Luigi; Longnecker, Richard; Smith, Greg; Studer, Lorenz; Casanova, Jean-Laurent; Zhang, Shen-Ying
Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.
Open Access
Immunodeficiency associated with a novel functionally defective variant of SLC19A1 benefits from folinic acid treatment
(Springer Nature, 2022-12-15) Gök, V.; Erdem, Ş.; Haliloğlu, Y.; Bişgin, A.; Belkaya, Serkan; Başaran, K. E.; Canatan, M. F.; Özcan, A.; Yılmaz, E.; Acıpayam, C.; Karakükcü, M.; Canatan, H.; Per, H.; Patıroğlu, T.; Eken, A.; Ünal, E.
Insufficient dietary folate intake, hereditary malabsorption, or defects in folate transport may lead to combined immunodeficiency (CID). Although loss of function mutations in the major intestinal folate transporter PCFT/SLC46A1 was shown to be associated with CID, the evidence for pathogenic variants of RFC/SLC19A1 resulting in immunodeficiency was lacking. We report two cousins carrying a homozygous pathogenic variant c.1042 G > A, resulting in p.G348R substitution who showed symptoms of immunodeficiency associated with defects of folate transport. SLC19A1 expression by peripheral blood mononuclear cells (PBMC) was quantified by real-time qPCR and immunostaining. T cell proliferation, methotrexate resistance, NK cell cytotoxicity, Treg cells and cytokine production by T cells were examined by flow cytometric assays. Patients were treated with and benefited from folinic acid. Studies revealed normal NK cell cytotoxicity, Treg cell counts, and naive-memory T cell percentages. Although SLC19A1 mRNA and protein expression were unaltered, remarkably, mitogen induced-T cell proliferation was significantly reduced at suboptimal folic acid and supraoptimal folinic acid concentrations. In addition, patients’ PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1. This study presents the second pathogenic SLC19A1 variant in the literature, providing the first experimental evidence that functionally defective variants of SLC19A1 may present with symptoms of immunodeficiency.
Open Access
Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children
(American Association for the Advancement of Science (AAAS), 2022-12-20) Lee, D.; Pen, J. L.; Yatim, A.; Dong, B.; Aquino, Y.; Ogishi, M.; Pescarmona, R.; Talouarn, E.; Rinchai, D.; Zhang, P.; Perret, M.; Liu, Z.; Jordan, L.; Bozdemir, S. E.; Bayhan, G. I.; Beaufils, C.; Bizien, L.; Bisiaux, A.; Lei, W.; Hasan, M.; Chen, J.; Gaughan, C.; Asthana, A.; Libri, V.; Luna, Joseph M.; Jaffré, Fabrice; Hoffmann, H.; Michailidis, E.; Moreews, M.; Seeleuthner, Y.; Bilguvar, K.; Mane, S.; Flores, C.; Zhang, Y.; Arias, A. A.; Bailey, R.; Schlüter, A.; Milisavljevic, B.; Bigio, B.; Voyer, T. L.; Materna, M.; Gervais, A.; Moncada-Velez, M.; Pala, F.; Lazarov, T.; Levy, R.; Neehus, A.; Rosain, J.; Peel, J.; Chan, Y.; Morin, M.; Pino-Ramirez, R. M.; Belkaya, Serkan; Lorenzo, L.; Anton, J.; Delafontaine, S.; Toubiana, J.; Bajolle, F.; Fumadó, V.; DeDiego, M. L.; Fidouh, N.; Rozenberg, F.; Pérez-Tur, J.; Chen, S.; Evans, T.; Geissmann, F.; Lebon, P.; Weiss, S. R.; Bonnet, D.; Duval, X.; Cohort§, C.; Effort, C.; Pan-Hammarström, Q.; Planas, A. M.; Meyts, I.; Haerynck, F.; Pujol, A.; Sancho-Shimizu, V.; Dalgard, C.; Bustamante, J.; Puel, A.; Boisson-Dupuis, S.; Boisson, B.; Maniatis, T.; Zhang, Q.; Bastard, P.; Notarangelo, L.; Béziat, V.; Diego, R.; Rodriguez-Gallego, C.; Su, H. C.; Lifton, R. P.; Jouanguy, E.; Cobat, A.; Alsina, L.; Keles, S.; Haddad, E.; Abel, L.; Belot, A.; Quintana-Murci, L.; Rice, C. M.; Silverman, R. H.; Zhang, S.; Casanova, J.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
Open Access
Inherited Irak-4 deficiency in acute human Herpesvirus-6 encephalitis
(Springer, 2022-10-07) Tepe, Zeynep Güneş; Yazıcı, Yılmaz Yücehan; Tank, Umut; Köse, Ladin Işık; Özer, Murat; Aytekin, Caner; Belkaya, Serkan
Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient’s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient’s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.
Open Access
Isolated subcutaneous abscess: A rare presentation of extrapulmonary tuberculosis
(Lippincott Williams & Wilkins, 2023-08-01) Sahin, A.; Kara-Aksay, A.; Bicmen, C.; Belkaya, Serkan; Kaya, A.; Yilmaz, D.
Open Access
Rational design of monomeric IL37 variants guided by stability and dynamical analyses of IL37 dimers
(Research Network of Computational and Structural Biotechnology, 2024-04-22) Sardag, I.; Düvenci, Z.Ş.; Belkaya, Serkan; Timuçin, E.
IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response of IL18 by binding to IL18R𝛼, a capacity lost in its dimeric form, underlining the pivotal role of the oligomeric status of IL37 in its anti-inflammatory action. Until now, two IL37 dimer structures have been deposited in PDB, reflecting a substantial difference in their dimer interfaces. Given this discrepancy, we analyzed the PDB structures of the IL37 dimer (PDB IDs: 6ncu, 5hn1) along with a AF2-multimer prediction by molecular dynamics (MD) simulations. Results showed that the 5hn1 and AF2-predicted dimers have the same interface and stably maintained their conformations throughout simulations, while the recent IL37 dimer (PDB ID: 6ncu) with a different interface did not, proposing a possible issue with the recent IL37 dimer structure (6ncu). Next, focusing on the stable dimer structures, we have identified five critical positions of V71/Y85/I86/E89/S114, three new positions compared to the literature, that would reduce dimer stability without affecting the monomer structure. Two quintuple mutants were tested by MD simulations and showed partial or complete dissociation of the dimer. Overall, the insights gained from this study reinforce the validity of the 5hn1 and AF2 multimer structures, while also advancing our understanding of the IL37 dimer interface through the generation of monomer-locked IL37 variants.
Open Access
sncRNA-1 is a small noncoding RNA produced by Mycobacterium tuberculosis in infected cells that positively regulates genes coupled to oleic acid biosynthesis
(Frontiers Media S.A., 2020-06) Coşkun, F. S.; Srivastava, S.; Raj, P.; Dozmorov, I.; Belkaya, Serkan; Mehra, S.; Golden, N. A.; Bucsan, A. N.; Chapagain, M. L.; Wakeland, E. K.; Kaushal, D.; Gumbo, T.; van Oers, N. S. C.
Nearly one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). While much work has focused on the role of different Mtb encoded proteins in pathogenesis, recent studies have revealed that Mtb also transcribes many noncoding RNAs whose functions remain poorly characterized. We performed RNA sequencing and identified a subset of Mtb H37Rv-encoded small RNAs (<30 nts in length) that were produced in infected macrophages. Designated as smaller noncoding RNAs (sncRNAs), three of these predominated the read counts. Each of the three, sncRNA-1, sncRNA-6, and sncRNA-8 had surrounding sequences with predicted stable secondary RNA stem loops. Site-directed mutagenesis of the precursor sequences suggest the existence of a hairpin loop dependent RNA processing mechanism. A functional assessment of sncRNA-1 suggested that it positively regulated two mycobacterial transcripts involved in oleic acid biosynthesis. Complementary loss- and gain- of-function approaches revealed that sncRNA-1 positively supports Mtb growth and survival in nutrient-depleted cultures as well as in infected macrophages. Overall, the findings reveal that Mtb produces sncRNAs in infected cells, with sncRNA-1 modulating mycobacterial gene expression including genes coupled to oleic acid biogenesis.
Open Access
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.