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    Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism
    (Galenos Publ House, 2023) Ciftci, Nurdan; Akinci, Aysehan; Akbulut, Ekrem; Camtosun, Emine; Dundar, Ismail; Dogan, Mustafa; Kayas, Leman
    Objective: Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups-Kalman syndrome and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing with nexrt generation sequencing (NGS) is required for patients without typical phenotypic findings. The aim was to determine the genetic etiologies of patients with IHH using NGS, including 54 IHH-associated genes, and to present protein homology modeling and protein stability analyzes of the detected variations.Methods: Clinical and demographic data of 16 patients (eight female), aged between 11.6-17.8 years, from different families were assessed. All patients were followed up for a diagnosis of nIHH, had normal cranial imaging, were without anterior pituitary hormone deficiency other than gonadotropins, had no sex chromosome anomaly, had no additional disease, and underwent genetic analysis with NGS between the years 2008-2021. Rare variants were classified according to the variant interpretation framework of the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology. Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed.Results: Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the GNRHR gene, one (6.25%) had a compound heterozygous [likely pathogenic-variants of uncertain significance (VUS)] variant in PROK2 and four (25%) each had a heterozygous (VUS) variant in HESX1, FGF8, FLRT3 and DMXL2. Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH.Conclusion: The frequency of variation detection was similar to the literature. Modelling showed that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.
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    Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism (vol 15, pg 160, 2023)
    (Galenos Publ House, 2023) Ciftci, Nurdan; Akinci, Aysehan; Akbulut, Ekrem; Camtosun, Emine; Dundar, Ismail; Dogan, Mustafa; Kayas, Leman
    [Abstract Not Available]
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    Endoplasmic reticulum aminopeptidase-1 polymorphism increases the risk of rheumatoid arthritis
    (Walter De Gruyter Gmbh, 2022) Akbulut, Ekrem; Yildirim, Tulay; Ozturk, Onur
    Objectives Endoplasmic reticulum aminopeptidase-1 (ERAP1) polymorphic changes cause autoimmunity. To understand the contribution of ERAP1 to the occurrence of rheumatoid arthritis (RA) disease, we investigated the relationship between ERAP1 and RA. Methods This study was conducted with 201 patients and 171 healthy controls. The rs26653, rs27044, rs27582, rs28096, and rs30187 polymorphic regions of ERAP1 were investigated. The comparison was done with Arlequin software and logistic regression. Haplotypes were analyzed with Phylogenetic Network software. ERAP1 was modeled using Promod3. Topological changes in ERAP1 were analyzed with TM-Score. Results The results showed that rs26653G>C (p=0.002, OR=2.001, 95%CI=1.276-3.137), rs27044C>G (p=0.037, OR=1.583, 95%CI=1.028-2.440), rs27582G>A (p<0.05, OR=0.348, 95%CI=0.194-0.622) and rs30187C>T (p=0.006, OR=1.849, 95%CI=1.191-2.870) polymorphisms are associated with RA disease risk. The relationship between rs28096 polymorphism and RA disease risk could not be determined (p=0.509). The risk haplotype for rheumatoid arthritis was determined as [CGAAT]. It was determined that polymorphisms of ERAP1 cause changes in the entry pocket of substrate and ligand. Conclusions We report a haplotype [CGAAT] that is associated with RA risk from Turkey that has not been described before. These data will make important contributions to elucidating the molecular mechanism of RA.
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    The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis
    (Walter De Gruyter Gmbh, 2022) Akbulut, Ekrem; Yolbas, Servet; Ozgen, Metin
    Objectives: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that mainly affects the axial skeleton. Peroxisome proliferator activated receptor alpha (PPARA) is an intracellular transcription factor, which play a role in inflammation and osteoblasting activity. This study is designed to investigate the relationship of NG_012204.2:p.A1a268Val polymorphism of PPARA with axSpA risk and its role in disease development. Methods: This study was conducted with 168 patients and 181 controls. Genotyping was done with MALDITOF. Gene expression level was analyzed by quantitative real time PCR (RT-qPCR). The protein homology models of PPARA were created with ProMod3. Ligand binding dynamics were tested using the AutoDock4 docking program. Statistical evaluations were made with SPSS (ver24) and GeneGlobe. Results: Our results showed that C>T polymorphism causing NG_012204.2:p.A1a268Val change was associated with disease risk (p=0.024) and T allele increased disease risk 1.7 times (95% CI=1.070-2.594). PPARA expression decreased (p<0.05) in individuals carrying the T allele. We determined that the ligand entry pocket was opened 1.1 A in the polymorphic PPARA. Polymorphic change caused a decrease in the ligand binding affinity. Conclusions: Our results provide an important contribution to elucidating the development of axSpA and demonstrate the potential of PPARA as a marker for the diagnosis of axSpA.