Determination of Deleterious SNPs in NUDT15 Gene Related to Acute Lymphoblastic Leukemia by using Bioinformatics Tools

Öz

Aim: In acute lymphoblastic leukemia (ALL), thiopurine group drugs are the most basic drugs and are included in almost all treatment protocols, especially in maintenance treatment. The mechanism of action of thioguanine nucleotides is to enter the DNA structure in cells, disrupt DNA synthesis, and trigger programmed cell death. The impact of deleterious SNPs on nucleotide triphosphate diphosphatase protein regarding ALL is not yet fully understood. In this study, it was aimed to determine the possible deleterious impacts of missense variants in the NUDT15 gene on protein structure and stabilization that play a significant role in susceptibility to the disease, using modern bioinformatics software. Method: To access SNPs in the NUDT15, it was used National Center for Biotechnology Information (NCBI), Single Nucleotide Polymorphism Database (dbSNP). In bioinformatics tools used in this study included SIFT, PolyPhen-2, PROVEAN, SNAP2, and PANTHER, followed by I-Mutant, HOPE, and STRING. Results: The results of the analysis showed that in a total of 6663 SNPs in the NUDT15, 6 variants have been identified as ‘deleterious’. According to the I-Mutant software, 4 deleterious SNPs decreased protein stability while 2 deleterious SNPs increased protein stability. In the HOPE database analysis, E115G, E57G, F52L, and K33N mutant amino acids were found to be smaller and more hydrophobic than wild-type amino acids, while G53R and G145D mutant amino acids were found to be larger. Thus, all variations resulted in alterations in the net charge on the NUDT15 protein. Conclusion: Data on NUDT15 variants will contribute to the prediction of the patient’s response to thiopurine drugs in future studies, to a better understanding of the patient’s susceptibility to drug interactions, and ultimately to obtaining information about the prognosis.

Anahtar Kelimeler

• Leukemia
• single nucleotide polymorphism
• thiopurine

Akut Lenfoblastik Lösemi ile İlişkilendirilen NUDT15 Genindeki Zararlı SNP’lerin Biyoinformatik Araçlar Kullanılarak Belirlenmesi

Öz

Amaç: Akut lenfoblastik lösemide (ALL) tiopurin grubu ilaçlar en temel ilaçlardır ve idame tedavisi başta olmak üzere hemen hemen tüm tedavi protokollerinde yer almaktadır. Tiyoguanin nükleotitlerinin etki mekanizması hücrelerde DNA yapısına girmek, DNA sentezini bozmak ve programlı hücre ölümünü tetiklemektir. Zararlı tek nükleotid polimorfizmlerin (SNP’lerin) ALL ile ilgili nükleotid trifosfat difosfataz proteini üzerindeki etkisi henüz tam olarak anlaşılmamıştır. Bu çalışmada, NUDT15 genindeki yanlış anlamlı varyantların hastalığa yatkınlıkta önemli rol oynayan protein yapısı ve stabilizasyonu üzerine olası zararlı etkilerinin modern biyoinformatik yazılımları kullanılarak belirlenmesi amaçlanmıştır. Yöntem: NUDT15 genindeki SNP’lere erişmek için Ulusal Biyoteknoloji Bilgi Merkezi (NCBI), Tek Nükleotid Polimorfizm Veritabanı (dbSNP) kullanılmıştır. Bu çalışmada SIFT, PolyPhen-2, PROVEAN, SNAP2, PANTHER, I-Mutant, HOPE ve STRING biyoinformatik araçlarının kullanımı yer almıştır. Bulgular: Analiz sonuçları, NUDT15 genindeki toplam 6663 SNP’de 6 varyantın ‘zararlı’ olarak tanımlandığını göstermiştir. I-Mutant yazılımına göre 4 zararlı SNP protein stabilitesini azaltırken 2 zararlı SNP protein stabilitesini arttırmıştır. HOPE veri tabanı analizinde E115G, E57G, F52L ve K33N mutant amino asitlerinin yabanıl tip amino asitlere göre daha küçük ve hidrofobik olduğu, G53R ve G145D mutant amino asitlerinin ise daha büyük olduğu tespit edilmiştir. Bu sebeple, tüm varyasyonlar NUDT15 proteini üzerindeki net yükte değişiklikle sonuçlanmıştır. Sonuç: NUDT15 varyantlarına ilişkin veriler, gelecekteki çalışmalarda hastanın tiopürin ilaçlarına yanıtının tahmin edilmesine, hastanın ilaç etkileşimlerine duyarlılığının daha iyi anlaşılmasına ve nihayetinde prognoz hakkında bilgi edinilmesine katkı sağlayacaktır.

Anahtar Kelimeler

• Lösemi
• tek nükleotid polimorfizm
• tiyopurin

Kaynakça

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