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Öğe 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, LemanObjective: 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.Öğe Effect of adiponectin on a disintegrin and metalloproteinase with thrombospondin motifs-9 gene expression in human chondrocytes(Amer Assoc Immunologists, 2014) Yaykasli, Kursat; Dogan, Mustafa; Hatipoglu, Omer; Yaykasli, Emine; Kaya, Ertugrul; Ozsahin, Mustafa; Uslu, Mustafa[Abstract Not Available]Öğe Leptin induction of aggrecanases-1 and-2 genes expression in human chondrocytes is mediated by p38 mitogen-activated protein kinase pathway(Amer Assoc Immunologists, 2014) Hatipoglu, Omer; Yaykasli, Kursat; Dogan, Mustafa; Yaykasli, Emine; Kaya, Ertugrul; Ozsahin, Mustafa; Usiu, Mustafa[Abstract Not Available]Öğe NF-?B and MAPKs are involved in resistin-caused ADAMTS-5 induction in human chondrocytes(Canadian Soc Clinical Investigation, 2015) Hatipoglu, Omer F.; Yaykasli, Kursat O.; Dogan, Mustafa; Yaykasli, Emine; Bender, Onur; Yasar, Tugce; Tapan, SafaPurpose: Chronic inflammation is an important etiological factor in the development of arthritic diseases. Several factors contribute to aggregation of chronic inflammation, including the presence of excess adipose tissue. Methods: The putative induction mechanisms of ADAMTS-5 by resistin were investigated in normal primary human articular chondrocytes. Expression levels of the ADAMTS-5 gene were determined at several resistin doses and durations. Results: Human chondrocytes were activated and associated with upregulated ADAMTS-5 gene expression after exposure to resistin (also known as adipose tissue-specific secretary factor, ADSF). Release of ADAMTS-5 leads to joint cartilage degradation, a key event in the development of arthritic diseases rheumatoid arthritis (RA) and osteoarthritis (OA). Activation of chondrocytes was associated with upregulated NF-kappa B protein levels in a time-dependent fashion. Co-incubation of human chondrocytes with JNK and p38 inhibitors lead to abrogated levels of NF-kappa B, indicating that these MAPKs are important in the activation of chondrocytes after stimulation with resistin. Similarly, ADAMTS-5 expression levels were abrogated when co-incubated with p38, NF-kappa B, JNK, MEK and PI3K inhibitors. Our results demonstrate that resistin, released from adipose tissue, may be involved in the development of RA and OA in obese patients through degradation of joint cartilage via ADAMTS-5 released from activated chondrocytes.Öğe Visfatin increases the activity of aggrecanases-1 and-2 in human chondrocytes(Amer Assoc Immunologists, 2014) Yaykasli, Kursat; Dogan, Mustafa; Hatipoglu, Omer; Yaykasli, Emine; Kaya, Ertugrul; Ozsahin, Mustafa; Uslu, Mustafa[Abstract Not Available]
