Turkiye Klinikleri Journal of Medical Sciences

.: ORIGINAL RESEARCH
Embriyonik Beyin Gelişiminde Görevli DCX ve PAFAH1B1 Genlerinde Meydana Gelen SNP'lerin İn Silico Değerlendirilmesi: Biyoinformatik Çalışma
In Silico Evaluation of SNPs Occurring in DCX and PAFAH1B1 Genes Involved in Embryonic Brain Development: Bioinformatic Study
Ahmet TAMERa
aÜsküdar Üniversitesi Sağlık Bilimleri Enstitüsü, Nörobilim ABD, İstanbul, Türkiye
Turkiye Klinikleri J Med Sci. 2022;42(2):119-29
doi: 10.5336/medsci.2021-86727
Article Language: TR
Full Text
ÖZET
 Amaç: DCX geni, sinir sisteminin gelişimi sırasında nöronların mikrotübüllerine bağlanan doublecortin proteinini kodlamaktadır. Doublecortin, göç eden nöronlarda mikrotübülleri bağlar ve stabilize eder. Bu gen ailesinin üyeleri tarafından düzenlenen hücresel süreçler; nöronal göç, nörogenez ve göz reseptör gelişimini de içermektedir. PAFAH1B1 geni nöronal göç sırasında hücre nükleusunun göçünden sorumludur. Literatürde bu genlerde tek nükleotid polimorfizmlerinin etkilerini in silico analizlerle bildiren bir çalışma kaydedilmemiştir. Bu araştırmanın amacı çeşitli hücresel süreçleri düzenleyen Doublecortin-X (DCX) ve PAFAH1B1 genlerindeki tek nükleotid polimorfizmlerinin in silico analizlerle değerlendirilmesidir. Gereç ve Yöntemler: Bu çalışmada DCX ve PAFAH1B1 genlerinde oluşan SNP'lerin, bu genlerin kodladıkları proteinlerin fonksiyonel etkileri, stabilite analizleri ve modellemeleri; SIFT, PolyPhen, Provean, PhD-SNP, Mutation assesor, SNPs&GO, SNAP2, I-Mutant 3.0, MuPro, HOPE veritabanları ile yapıldı. GeneMANIA ile bu genlerin diğer genlerle etkileşimde olduğu gösterildi. Bu genlerdeki mikroRNA işlevlerinin, merkezi sinir sisteminde oluşan hastalıklarla ilişkisine bakmak için Human Disease MicroRNA Database 3.0 kullanıldı. Bulgular: Çeşitli veri tabanları ile yapılan bu çalışmada DCX ve PAFAH1B1 genlerindeki SNP'lerin protein fonksiyonuna zararlı olduğu, stabilite analizlerinde protein kararlılığının bozulmasına neden olduğu sonucuna ulaşıldı. Proteinlerde boyut, yük ve hidrofobisite farklılığı oluştuğu sonucuna ulaşıldı. Sonuç: Boyut, yük ve hidrofobisite değişimi proteinlerin çekirdeğine uyum sağlayamamasına, yük farkıyla etkileşimde olduğu molekülleri iteceği ve hidrofobisite farkından dolayı hidrojen bağlarının doğru pozisyonda oluşamamasına dolayısıyla protein katlanma sorunlarına yol açabileceği sonucuna ulaşıldı. GeneMANIA ile bu genlerin birçok genle etkileşimde olup, çeşitli süreçleri düzenlediği ve bu genlerin mikroRNA'larında değişimin şizofreni, otizm, glioblastoma, beyin neoplazmaları, iskemi, epilepsi, nöroblastoma gibi merkezi sinir sistemi hastalıklarıyla ilişkili olduğu gösterildi.

Anahtar Kelimeler: DCX ve PAFAH1B1 geni; kortikal malformasyonlar; tek nükleotid polimorfizmi; in silico
ABSTRACT
 Objective: The DCX gene encodes the doublecortin protein that binds to the microtubules of neurons during the development of the nervous system. Doublecortin binds and stabilizes microtubules in migrating neurons. Cellular processes regulated by members of this gene family; it also includes neuronal migration, neurogenesis and eye receptor development. The PAFAH1B1 gene is responsible for the migration of the cell nucleus during neuronal migration. There is no study in the literature reporting the effects of single nucleotide polymorphisms in these genes by in silico analysis. The aim of this research is to evaluate single nucleotide polymorphisms in Doublecortin-X (DCX) and PAFAH1B1 genes, which regulate various cellular processes, by in silico analysis. Materials and Methods: In this study, the functional effects, stability analyzes and modeling of the SNPs formed in DCX and PAFAH1B1 genes and the proteins encoded by these genes; SIFT, PolyPhen, Provean, PhD-SNP, Mutation assessor, SNPs&GO, SNAP2, I-Mutant 3.0, MuPro, HOPE databases. These genes were shown to interact with other genes with GeneMANIA. Human Disease MicroRNA Database 3.0 was used to look at the relationship between microRNA functions in these genes and diseases in the central nervous system. Findings: In this study conducted with various databases, SNPs in DCX and PAFAH1B1 genes are harmful to protein function, in stability analyzes, it was concluded that it caused deterioration of protein stability. It was concluded that there were differences in dimension, charge and hydrophobicity in proteins. Conclusion: It was concluded that the change in dimension, charge and hydrophobicity may cause the proteins to not adapt to their nuclei, repel the molecules with which they interact with the charge difference, and the hydrogen bonds cannot be formed in the correct position due to the hydrophobicity difference, thus leading to protein folding problems. With GeneMANIA, it has been shown that these genes interact with many genes and regulate various processes, and that changes in the microRNAs of these genes are associated with central nervous system diseases such as schizophrenia, autism, glioblastoma, brain neoplasms, ischemia, epilepsy, and neuroblastoma.

Keywords: DCX and PAFAH1B1 gene; cortical malformation; single nucleotide polymorphism; in silico
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