Mefv gen mutasyonları taşıyan bireylerde yeni nesil dizileme yöntemi ile elde edilmiş yaygın ve yeni varyantların veri tabanlarında analizleri: retrospektif çalışma
Loading...
Files
Date
2019
Authors
Kurt, Zeynep
Journal Title
Journal ISSN
Volume Title
Publisher
Bursa Uludağ Üniversitesi
Abstract
MEFV geni 16. Kromozomun kısa kolu üzerinde 115 kb’lık bir bölge üzerindedir. Bu gen yaklaşık 3.7 kb uzunluğunda bir transkript kodlar. Genin ürünü 781 aminoasitlik pirin proteinidir. Pirin sadece olgun granülositlerde ifade olur. Pirinin görevi nötrofil aktivasyonunu azaltıp inflamasyonu baskılamaktır. Pirinin dört domaininden biri olanB30.2’dur. B30.2 bölgesinin ekspresyonu ile kaspaz-1 aktivasyonu olur ve IL-1b üretimini azaltır. Pirin mutasyona uğrayınca sıradan uyarıcılara cevap olarak aşırı derecede IL-1b üretimine neden olur. Çalışmalar atak döneminde İnterlökin IL–2, IL–6, IL–8 veTümör Nekroz Faktör-alfa (TNF-α) düzeylerinin yüksek olduğu saptanmıştır.FMF (familial mediterranean fever) hastalığı MEFV genindeki mutasyonlar sonucu ortaya çıkan otoinflamatuar hastalıkların en sık görülenidir. Hastalık ani başlayan ateş ve seröz zarların inflamasyonu ile karakterizedir. Akdeniz çevresinde yaygın olan hastalık Seferadik Yahudier, Ermeniler, Araplar ve Türkler arasında yaygındır. Bu çalışmanın amacı FMF hastalığına sebep olan MEFV geni varyantlarını tespit etmek, sınıflandırmak ve yeni varyantlar tespit edip varyant sınıflandırmasına kazandırmaktır. Çalışmaya katılan 673 erkek, 841 kadın toplam 1514 hastadan alınan kan örnekleriyle NGS dizilime yardımıyla gen analizi yapılmıştır. Sophia DDM progamıyla analizisonucun da 75 tanesi ekzonda 29 tanesi intronda olmak üzere 104 varyant tespit edilmiştir. Tespit edilen bu varyantların 7 tanesi ekzonik 6 taneside intronik olmak üzere 13 tanesi novel varyanttır. Sonra elde edilen bu varyantlar çeşitli insilico analizler kullanarak patojenik özellikte olup olmadığına göre çeşitli sınıflandırmalara tabi tutulmuştur. Ayrıca birçok veritabanıyla analiz edilerek posttranslasyonel modifikasyonlarda rolü olup olmadığı anlaşılmaya çalışılmıştır. Elde edilen varyantların allel frekansı üzerine çalışılarak ne kadar sıklıkla görüldüğü hakkında bilgi edinilmeye çalışılmıştır.
The MEFV gene is located on the short arm of chromosome 16 spanning a region of 115 kb in human. This gene encodes a transcript of approximately 3.7 kb. The product of this gene encodes 781 amino acid pyrin protein. Pyrin is expressed only in mature granulocytes. The major function of pyrin is to reduce neutrophil activation and suppress inflammation. B30.2, one of the four domains of pyrin; interacts with caspase- 1. It reduces activation of caspase-1 and production of IL-1b. Excessive production of IL-1b in response to ordinary stimuli has been recorded on pyrin mutations. Interleukin IL –2, IL-6, IL-8 and Tumor Necrosis Factor-alpha (TNF-α) levels were found to be high during the attack period. FMF (Familial Mediterranean Fever) is one of the most common auto-inflammatory diseases caused by mutations in the MEFV gene. The disease is characterized by sudden onset of fever and inflammation of serous membranes. FMF is widespread in the Mediterranean region and common especially among Sephardic Jews, Armenians, Arabs and Turks. The aim of this study was to identify and classify MEVF gene variants in Turkish FMF patients using in silico tools. Novel variants are also determined and classified in this context. Sequencing of the gene is performed using Next Generation Sequencing. DNA was obtained from peripheral blood samples obtained from 1514 patients (673 males and 841 females). Initial data were analyzed with Sophia DDM program. As a result, 104 variants were detected. 75 of them were located in exons and 29 in introns. Of these variants, 13 were novel (7 exonic and 6 intronic). These variants were then subjected to various classifications according to their pathogenicity using various in silico analyzes. In addition, the amino acid changes have been analyzed using web tools to determine whether these changes have a role in post-translational modifications. Lastly, allele frequencies of the variants were calculated and compared to the previous data in the literature.
The MEFV gene is located on the short arm of chromosome 16 spanning a region of 115 kb in human. This gene encodes a transcript of approximately 3.7 kb. The product of this gene encodes 781 amino acid pyrin protein. Pyrin is expressed only in mature granulocytes. The major function of pyrin is to reduce neutrophil activation and suppress inflammation. B30.2, one of the four domains of pyrin; interacts with caspase- 1. It reduces activation of caspase-1 and production of IL-1b. Excessive production of IL-1b in response to ordinary stimuli has been recorded on pyrin mutations. Interleukin IL –2, IL-6, IL-8 and Tumor Necrosis Factor-alpha (TNF-α) levels were found to be high during the attack period. FMF (Familial Mediterranean Fever) is one of the most common auto-inflammatory diseases caused by mutations in the MEFV gene. The disease is characterized by sudden onset of fever and inflammation of serous membranes. FMF is widespread in the Mediterranean region and common especially among Sephardic Jews, Armenians, Arabs and Turks. The aim of this study was to identify and classify MEVF gene variants in Turkish FMF patients using in silico tools. Novel variants are also determined and classified in this context. Sequencing of the gene is performed using Next Generation Sequencing. DNA was obtained from peripheral blood samples obtained from 1514 patients (673 males and 841 females). Initial data were analyzed with Sophia DDM program. As a result, 104 variants were detected. 75 of them were located in exons and 29 in introns. Of these variants, 13 were novel (7 exonic and 6 intronic). These variants were then subjected to various classifications according to their pathogenicity using various in silico analyzes. In addition, the amino acid changes have been analyzed using web tools to determine whether these changes have a role in post-translational modifications. Lastly, allele frequencies of the variants were calculated and compared to the previous data in the literature.
Description
Keywords
FMF, MEFV gene, MEFV geni, Kaspaz-1, İnterlökin, Caspase-1, Interleukin
Citation
Kurt, Z. (2019). Mefv gen mutasyonları taşıyan bireylerde yeni nesil dizileme yöntemi ile elde edilmiş yaygın ve yeni varyantların veri tabanlarında analizleri: Retrospektif çalışma. Yayınlanmamış yüksek lisans tezi. Bursa Uludağ Üniversitesi Fen Bilimleri Enstitüsü.