Eda Tahir Turanli - Academia.edu (original) (raw)

Papers by Eda Tahir Turanli

Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype

Rheumatology

Objective The presence of FMF cases without MEFV (MEFV innate immunity regulator, pyrin) pathogen... more Objective The presence of FMF cases without MEFV (MEFV innate immunity regulator, pyrin) pathogenic variants led us to search for other genes’ involvement in the disease development. Here, we describe the presence of genetic heterogeneity in a three-generation family with an FMF/mevalonate kinase deficiency (MKD)-overlapping phenotype without MEFV/MVK (mevalonate kinase) pathogenic variants. Method Targeted sequencing revealed a rare, fully penetrant variant in PSTPIP1 (p.Arg228Cys, rs781341816). Computational stability analyses of PSTPIP1 protein were performed. PSTPIP1-pyrin protein interaction was examined by immunoprecipitation and immunoblotting in peripheral blood mononuclear cells (PBMCs) of patients and healthy controls. PBMCs were cultured, and inflammation was induced by LPS+ATP treatment, followed by protein level measurements of caspase-1, IL1ß, pyrin and PSTPIP1 in cell lysates and mature caspase-1 and mature IL1ß in supernatants. Results The conserved, rare (GnomAD, 0....

Biology

The blind mole rat (BMR), a long-living subterranean rodent, is an exceptional model for both agi... more The blind mole rat (BMR), a long-living subterranean rodent, is an exceptional model for both aging and cancer research since they do not display age-related phenotypes or tumor formation. The Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling is a cytokine-stimulated pathway that has a crucial role in immune regulation, proliferation, and cytokine production. Therefore, the pathway has recently attracted interest in cellular senescence studies. Here, by using publicly available data, we report that JAK–STAT signaling was suppressed in the BMR in comparison to the mouse. Interestingly, our experimental results showed upregulated Jak1/2 expressions in BMR fibroblasts during the replicative senescence process. The transcriptomic analysis using publicly available data also demonstrated that various cytokines related to JAK–STAT signaling were upregulated in the late passage cells, while some other cytokines such as MMPs and SERPINs were downregulated, re...

Genome-wide analysis of schizophrenia and multiple sclerosis identifies shared genomic loci with mixed direction of effects

Brain, Behavior, and Immunity

Frontiers in Aging

Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence ... more Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.

Journal of Pharmaceutical Analysis, 2021

The pandemic caused by the worldwide spread of the coronavirus, which first appeared in 2019, has... more The pandemic caused by the worldwide spread of the coronavirus, which first appeared in 2019, has been named coronavirus disease 19 (COVID-19). More than 4.5 million deaths have been recorded due to the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), according to the World Health Organization. COVID-19 Dashboard in September 2021. Apart from the wildtype, other variations have been successfully transmitted early in the outbreak although they were not discovered until March 2020. Modifications in the SARS-CoV-2 genetic material, such as mutation and recombination, have the ability to modify the viral life span, along with transitivity, cellular tropism, and symptom severity. Several processes are involved in introducing novel vaccines to the population, including vaccine manufacturing, preclinical studies, Food and Drug Administration permission or certification, processing, and marketing. COVID-19 vaccine candidates have been developed by a number of public and private groups employing a variety of strategies, such as RNA, DNA, protein, and viral vectored vaccines. This comprehensive review, which included the most subsequent evidence on unique features of SARS-CoV-2 and the associated morbidity and mortality, was carried out using a systematic search of recent online databases in order to generate useful knowledge about the COVID-19 updated versions and their consequences on the disease symptoms and vaccine development.

Rheumatology International, 2019

Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Investigation o... more Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Investigation of proteome profiles of disease specific cells facilitates our understanding of the processes and related molecular pathways, especially in disorders like BS with complex inheritance pattern and clinical heterogeneity. In the current study, we evaluated the peripheral blood mononuclear cells (PBMCs) proteome of 59 patients with BS (33 in active and 26 in inactive phases) and of 28 healthy controls using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed protein spots with at least twofold and/or statistically significant change (p ≤ 0.05) between active BS vs inactive BS, and also active BS vs healthy controls were identified by mass spectrometry (MALDI-TOF/TOF). Bioinformatic analyses revealed 16 differentially expressed proteins (12 of them in active vs inactive BS comparison, whereas 11 of them for active BS vs healthy control comparison) belonging to glycolysis, cytoskeleton organization, protein folding, and regulation of blood coagulation pathways. Stathmin (active BS vs inactive BS; fourfold, active BS vs healthy control; 4.7-fold) and WD repeat-containing protein-1 (active BS vs inactive BS; 2.7-fold, active BS vs healthy control; 2.7-fold), which are cytoskeleton-related proteins, were found to be lower in active patients compared to inactive patients and healthy control. Decreased levels of calreticulin (active BS vs inactive BS; 1.29-fold) and heat shock 70 kDa protein 8 (active BS vs healthy control; 1.5-fold) which are involved in protein folding and endoplasmic reticulum (ER) stress process, were observed in patients with active phase of BS. Down-regulation of protein folding and ER stress process proteins in BS patients may further support the involvement of ER stress in BS.

Nephrology Dialysis Transplantation, 2019

European Journal of Paediatric Neurology, 2019

Objective: Neurologic complications of chronic infantile neurologic, cutaneous and articular synd... more Objective: Neurologic complications of chronic infantile neurologic, cutaneous and articular syndrome (CINCA) are well-known, whereas there are scarce data regarding neurologic features of milder cryopyrin-associated periodic syndrome (CAPS) phenotypes. We aimed to review the neurologic features in detail and summarize the other CAPS-related manifestations in 12 children. Methods: All children with CAPS that have been followed-up from pediatric rheumatology outpatient clinic, were enrolled to the study. In addition to the neurologic examination, magnetic resonance imaging (MRI) of brain, electroencephalography, eye examination, hearing test and intellectual assessment were done. Demographic, clinical features, genetic analysis and laboratory tests were noted from patient records and hospital database. Results: The median age of the subjects was 7 years (range 2-19 years), with a female-tomale ratio 2/1. The phenotype was consistent with familial cold autoinflammatory syndrome in 7 patients, Muckle-Wells syndrome in 3 patients and chronic infantile neurologic, cutaneous and articular syndrome in 2 patients. Most frequently noted neurologic clinical manifestation during the entire disease course was headache (n=4/12) followed by seizures (n=3/12), papilledema (n=3/12), intellectual disability (n=2/12), aseptic meningitis (n=2/12), hearing loss (n=2/12) and optic atrophy (n=1/12). MRI of the brain revealed abnormal lesions in two patients. Uveitis or conjunctivitis were seen in two children. Overall, neurological involvement was detected in 6/12 of our cohort, of which half (n=3) was in severe form. Conclusion: Half of the children with CAPS exhibited neurologic manifestations with varying degrees of severity. Increased understanding and awareness of this rare but treatable syndrome among neurologists is essential. If remains untreated and unrecognized, this autoinflammatory syndrome could lead to significant morbidity and mortality. Besides complete resolution of systemic symptoms, anti-interleukin-1 treatment may also prevent progression of neurologic findings when initiated in the early stage of the disease.

THURSDAY, 14 JUNE 2018, 2018

Thus, to estimate the risk of genetic variants of ABCG2 more comprehensively, we analysed the ass... more Thus, to estimate the risk of genetic variants of ABCG2 more comprehensively, we analysed the association between all exonic variants and gout susceptibility. Objectives: The main purpose of this study was to perform comprehensive in silico evaluation of the effects of all types of rare and common exonic ABCG2 variants on gout susceptibility in Japanese population. Methods: We previously sequenced all the exons of ABCG2 in 480 patients with gout and 480 healthy controls (Japanese males) and performed functional analyses of non-synonymous variants. In this present study, we analysed the correlation between urate transport function and scaled C-score of CADDv1.3 (CADD score) of non-synonymous variants. We additionally performed Receiver Operating Characteristic (ROC) curve analysis and selected variants with altered function of more than 50% compared to wild-type ABCG2. Stratified association analyses and multivariate logistic regression analysis were performed to evaluate the effects of selected rare and common ABCG2 variants on gout susceptibility. Results: We identified 4 common and 26 rare exonic or closely situated intronic variants of ABCG2. CADD scores showed significant correlation with the results of functional analyses on urate transport (p=0.014, r=À0.539). ROC curve analysis showed an area under the curve (AUC) of 0.775. The optimal cutoff value of CADD score was 15 for classifying variants with altered function of more than 50% compared to wild-type ABCG2 (sensitivity=0.88, specificity=0.67). Therefore, we selected variants with a CADD score greater than 15 for downstream analyses. All intronic or synonymous variants had low CADD scores and thus were removed. Multivariate logistic regression analysis showed that the rare variants of ABCG2 were associated with a significantly increased risk of gout and the size effect of these rare variants (odds ratio [OR]=2.7, p=0.012) was similar to that of the common variants, Q126X (OR=3.3, p=4.8×10-6) and Q141K (OR=2.3, p=8.6×10-1 6). Conclusions: This study confirmed that both common and rare variants in ABCG2 increase gout susceptibility. Furthermore, our in silico analyses suggest that synonymous and splice-site variants of ABCG2 may not play a key role in the pathogenesis of gout. REFERENCES: [1] T. Higashino, et al. Multiple common and rare variants of ABCG2 cause gout. RMD Open, 2017;3:e000464. [2] M. Kircher, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014:46(3):310-5.

Paediatrics and International Child Health, 2019

A 9.5-year-old boy was referred with a 2-year history of recurrent fever, myalgia, abdominal pain... more A 9.5-year-old boy was referred with a 2-year history of recurrent fever, myalgia, abdominal pain and various neurological manifestations associated with increased acute phase reactants and IgG level. During the recent episode, severe hypertension and right-sided hemiparesis developed and angiography demonstrated irregularities and stenosis in renal and mesenteric artery branches. Although these manifestations were consistent with polyarteritis nodosa (PAN), the consanguinity of his parents, a cousin with similar clinical features and early disease onset led to suspicion of deficiency of adenosine deaminase type 2 (DADA2) diseases. DADA2 was established by demonstration of decreased ADA2 enzyme activity and a homozygous G47R mutation in the CECR1 gene. The diagnosis of DADA2 is challenging because of the overlapping manifestations with PAN and other periodic fever syndromes. DADA2 should be considered in the differential diagnosis of PAN. Raised IgG levels (usually low in DADA2) should be sought in future cases.

Rheumatology international, Jan 17, 2017

Deficiency of adenosine deaminase type 2 (DADA2) is a rare form of autoinflammatory disorder with... more Deficiency of adenosine deaminase type 2 (DADA2) is a rare form of autoinflammatory disorder with limited reported cases. In this paper, we have presented the clinico-immunological, radiological and genetic characteristics of five surviving and three deceased childhood-onset DADA2 patients. We aimed to compare surviving and deceased patients in terms of clinical features and treatment modalities. Moreover, we have evaluated the causes of death in our DADA2 subjects together with the previously reported cases. Demographic features, clinical characteristics, imaging findings, mutations and pharmacological treatments of DADA2 subjects were noted from patient records of pediatric and adult rheumatology clinics in a retrospective and longitudinal nature. Eight patients from seven families were enrolled. While five of them were surviving, three of them had died due to various reasons. Median age of the patients at disease onset and diagnosis was 7 years (range 0.5-13 years) and 14 years (...

A twin study in Behçet's syndrome

Clinical and experimental rheumatology

Case reports on monozygotic (MZ) twins with Behçet's syndrome (BS) have been few and we are n... more Case reports on monozygotic (MZ) twins with Behçet's syndrome (BS) have been few and we are not aware of formal twin studies. We sought the frequency of MZ and dizygotic (DZ) twin births in BS and compared it to a healthy population sample from the same geography. We also looked for the concordance rate among the MZ and DZ twins. 1705 (1039M/666F) patients attending a dedicated BS outpatient clinic and 7761 (3848M/3913F) medical school students were asked about having a MZ or DZ twin sibling. MZ and DZ twins thus identified among both patients and controls were individually seen at the clinic. In addition, HLA, DNA microsatellite markers and blood groups were typed to further confirm twin- ship. All twins were contacted 8 years later for new emergence of disease. There were 14 (0.82%) patients with BS and 120 (1.55%) controls who had a twin sibling (p=0.022). Of these, 8 (0.47%) patients with BS and 92 (1.19%) controls had a DZ twin sibling (p=0.009). MZ twin frequency was simil...

Biomarkers for Phase Switches in Multiple Sclerosis

General Methods in Biomarker Research and their Applications, 2014

Objectives. To analyse the most common MEFV (Mediterranean fever gene) mutations and polymorphism... more Objectives. To analyse the most common MEFV (Mediterranean fever gene) mutations and polymorphisms in an elderly population free of chronic inflammatory disease (n=164), and explore possible associations between hsCRP (high sensitive C-reactive protein) and RF (rheumatoid factor) levels with MEFV mutations and polymorphisms. Methods. An elderly group free of chronic inflammatory disease was chosen among the outpatients of the division of geriatric medicine. Total genomic DNA was isolated from blood, and PCR-RFLP analysis was performed using established protocols. Sera were analyzed for hsCRP and RF levels. Results. The frequencies for 694V (1.8%), 694I (1.8%), 680I (0.6%), 726A (2.1%) and 148Q (5%) alleles were found to be similar to Turkish historic controls, with a carrier frequency of 1/4. Further analyses with rheumatoid factor (RF) levels and mutations revealed a significant association between the presence of the E148Q polymorphism with increased RF levels (>15 mg/dl) (χ 2 = 7.358, p=0.007, OR=5.41 95% CI 1.41-20.64). Conclusions. Common MEFV mutations and polymorphisms were similarly represented among the elderly population compared to historic controls. On the other hand, a significant association was found between the presence of E148Q polymorphism and increased RF levels. This suggests that the previously noted increased RF levels in elderly populations may somehow be related to the now described association of RF with MEFV E148Q polymorphism.

Functional promoter VNTR for MAOA: Identification of two novel alleles and analyses of association with neuroticism, depression and anxiety

Associations have been reported between a 30bp repeat polymorphism in the promoter region of MAOA... more Associations have been reported between a 30bp repeat polymorphism in the promoter region of MAOA and depressive disorders (e.g. Furlong et al., Am. J. Med. Genet., 1999), and panic disorder (Deckert et al., Hum. Molec. Genet., 1999). Analysis of the functionality of this marker revealed that alleles with 3.5 and 4 copies of the repeat are transcribed more efficiently than those with 3 or 5 (Sabol et al., Hum. Genet., 1998). We typed this marker in two independent samples. First, from a sample of 2085 adults, each assessed for neuroticism by two peers, we selected 57 individuals from the top 5% of scores, and 62 individuals from the bottom 5%. Using selected extreme low subjects rather than unselected controls gives roughly twice the power of a standard case-control design. Second, we are collecting DNA from adolescents diagnosed with anxiety or depressive disorders, and currently have 40 individuals in this sample, for the majority of which we also have parents. Exploratory analyses indicate higher prevalence of alleles with 3.5 and 4 repeats in the high neuroticism sample, particularly in males, although the differences do not reach statistical significance. Preliminary analyses of the family data do not indicate association between MAOA and anxiety and depressive disorders in adolescents, but sample collection is ongoing. On the basis of size analysis we have identified two novel alleles for the MAOA marker: 2.5 and 4.5 repeats.

Evaluation of the genes for the adrenergic receptors ?2A and ?1C and Gilles de la Tourette Syndrome

American Journal of Medical Genetics, 2003

Gilles de la Tourette Syndrome (GTS) has long been known to be familial, and evidence from twin s... more Gilles de la Tourette Syndrome (GTS) has long been known to be familial, and evidence from twin studies indicates that it has a substantial genetic component. Our genome scan of sibling pair families with GTS found evidence suggestive of linkage to several chromosomal locations. On the basis of these findings, we have begun to study additional markers in these regions, with some of the markers located in candidate genes. Two candidate genes stand out in these regions: the adrenergic receptor alpha 1C(1A) (ADRA1C) located on chromosome 8p and the adrenergic receptor alpha 2A (ADRA2A) located on chromosome 10q. The adrenergic system has been suggested to play a role in GTS based on the reduction of symptoms with the adrenergic receptor agonists, clonidine and guanfacine. We examined the inheritance of polymorphisms in the ADRA2A and ADRA1C genes in 113 nuclear families identified through a GTS proband. We found no significant evidence for linkage using the transmission disequilibrium test for these two genes. Based on our families, we conclude that these genes are not major genetic factors contributing to the susceptibility to GTS.

Scientific Reports

Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency a... more Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified; however, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the pres...

Behçet Hastalığı: Genetik ve Epigenetik Araştırmalar

Proteomic Analysis in CSF Identified Subtype Specific and Shared Molecular Pathways for Multiple Sclerosis Clinical Phenotypes (P5.216)

Neurology, 2015

Objective: The purpose of this study is to find out molecular pathways associated with the etiopa... more Objective: The purpose of this study is to find out molecular pathways associated with the etiopathogenesis of Multiple Sclerosis (MS) and its major subclinical pathways. To this aim proteomic and bioinformatics approaches were used to reveal the differentially expressed proteins and their related pathways in cerebrospinal fluids of patients with clinically isolated syndrome, relapsing remitting MS and progressive MS. Background: Phenotypic heterogeneity of MS appears to be cause by immune-mediated, neuro-inflammatory, demyelinating and neurodegenerative processes harboring complex molecular mechanisms. Design / Methods: CSF samples of 63-CIS, 72-RRMS, 44-PPMS and 42-controls including healthy subjects and other neurological disease samples were analyzed. For all samples, 2D-PAGE analyses were performed. At least four times differently expressed protein spots were identified by PDQuest® software and removed from the gel for MALDI-TOF-MS protein identification analysis. The results o...

Journal of Experimental Medicine, 2021

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its e... more Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, ...