Determination of Deleterious SNPs in APH1A Gene Related to Alzheimer’s Disease by In Silico Methods

Yıl 2019, , 472 - 480, 25.08.2019

Ebru Özkan Oktay , Tuğba Kaman , Ömer Faruk Karasakal , Korkut Ulucan , Muhsin Konuk , Nevzat Tarhan

https://doi.org/10.19113/sdufenbed.522738

Cited By: 3

Öz

Alzheimer's
disease (AD) is a progressive neurodegenerative disease characterized by
pathological accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary
tangles. γ-secretase produces the amyloid β peptide (Aβ), which causes AD.
γ-secretase is a macromolecular complex and the protein encoded by the APH1A
gene is located in this complex. In this study, it was aimed to determine the
possible deleterious effects of missense single nucleotide polymorphisms (SNPs)
in APH1A gene on the protein structure and stabilization via in silico methods. PolyPhen-2 and SIFT
were used to predict deleterious SNPs, I-Mutant 2.0 software was used to detect
protein stabilization changes and Project HOPE software tool was used to make
three-dimensional modeling of wild and mutant type proteins. The results showed
that 257 SNPs among a total of 3567 SNPs in the APH1A gene were missense SNPs.
According to the in silico analysis
of the 257 SNPs it has been determined that rs11548266, rs74126634,
rs145324799, rs199961673, rs370361277, rs370719475 and rs376071112
polymorphisms may have deleterious effects. The results of in silico analysis provide data for genotyping of SNPs which have
deleterious effects on protein structure and stabilization rather than
genotyping of entire 3567 SNPs in the APH1A gene associated with Alzheimer's
disease. Therefore, deleterious SNPs may be used in the selection of SNPs and
experimental design which are the most important stages of genotyping studies.
Thus, we envisaged that the obtained results will contribute to the further
studies either experimental or in silico
on Alzheimer's disease.

Anahtar Kelimeler

APH1A, Polymorphism, Alzheimer’s Disease, In silico

Alzheimer Hastalığı ile İlişkilendirilen APH1A Genindeki Zararlı SNP’lerin In Silico Yöntemler ile Belirlenmesi

Öz

Alzheimer
hastalığı (AH), β-amiloid (Aβ) senil plakların ve nörofibriler yumakların
patolojik birikimi ile karakterize olan ilerleyici bir nörodejeneratif
hastalıktır. γ-sekretaz, AH nedeni olan amiloid β peptidi (Aβ) üretmektedir.
γ-sekretaz makromoleküler bir komplekstir ve APH1A geninin kodladığı protein bu
komplekste yer almaktadır. Bu çalışmada, APH1A genindeki yanlış anlamlı
(missense) tek nükleotid polimorfizmlerinin (SNP) proteinin yapısı ve
stabilizasyonu üzerindeki olası zararlı etkilerinin in silico yöntemler kullanılarak belirlenmesi amaçlanmıştır.
Zararlı SNP’lerin tahmin edilmesi için PolyPhen-2 ve SIFT yazılım araçları,
protein stabilizasyonu değişimlerinin tespit edilmesi için I-Mutant 2.0
yazılımı, yabanıl ve mutant tip proteinlerin üç boyutlu modellemeleri için
Project HOPE yazılım aracı kullanılmıştır. Sonuçlar, APH1A geninde yer alan
toplam 3567 SNP’nin 257 tanesinin yanlış anlamlı SNP olduğunu göstermiştir. 257
SNP’nin in silico analizlerine göre,
rs11548266, rs74126634, rs145324799, rs199961673, rs370361277, rs370719475 ve
rs376071112 polimorfizmlerinin zararlı etkilerinin olabileceği belirlenmiştir.
Çalışmamızda gerçekleştirdiğimiz in
silico analizler, Alzheimer hastalığı ile ilgili APH1A geninde yer alan
3567 SNP’nin tamamının genotiplenmesi yerine proteinin yapısı ve
stabilizasyonuna zararlı etkisi olabilecek SNP’lerin genotiplenmesine ilişkin
veri sağlamaktadır. Dolayısıyla, zararlı olduğu tespit edilen SNP’ler
genotipleme çalışmalarının en önemli basamağı olan SNP seçiminde ve deney
tasarımında kullanılabilecektir. Bu nedenle, elde ettiğimiz sonuçların
Alzheimer hastalığı ile ilgili gelecekte yapılacak olan hem deneysel hem de in silico çalışmalara katkı sağlayacağı
düşünülmektedir.

Anahtar Kelimeler

APH1A, Polimorfizm, Alzheimer Hastalığı, In silico

Kaynakça

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