In-silico evaluation of single nucleotide polymorphisms in PSEN۱ gene in patients with Alzheimer's disease

Backgrounds: Alzheimer disease (AD) is a progressive neurodegenerative disease associatedwith cognitive decline and is the most common form of dementia characterized byneuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloidplaques that accumulate in vulnerable brain regions in the elderly. Approximately ۴۵% of peopleover the age of ۸۵ are estimated to have AD. Mutations in the PSEN۱ gene are the most commoncause of familial Alzheimer’s disease (FAD).Materials and Methods: We identified ten non-synonymous single nucleotide polymorphisms(nsSNPs) in the PSEN۱ gene: ((rs۶۳۷۴۹۸۰۵) (Phe۱۱۷Arg), (rs۶۳۷۴۹۸۳۵) (Leu۲۳۵Pro),(rs۶۳۷۴۹۸۸۰) (Gly۲۰۹Arg), (rs۶۳۷۴۹۹۶۲) (Tyr۱۱۵Asp), (rs۶۳۷۵۰۱۵۵) (Ser۱۷۸Pro),(rs۶۳۷۵۰۲۳۱) (Glu۲۸۰Ala), (rs۶۳۷۵۰۵۹۹) (Leu۸۵Pro), (rs۶۳۷۵۱۱۴۱) (Cys۹۲Ser), (rs۶۳۷۵۱۲۲۳)(Ala۴۲۶Pro), (rs۶۶۱) (Cys۴۱۰Tyr)) using dbSNP and then analyzed their effect on the structureof Presenilin ۱ protein using PyMOL and Expasy, pathogenicity and protein function throughPolyPhen-۲, SIFT and GVGD and stability by I-Mutant.Results: Our data from structural analysis showed that nsSNPs change the interaction patterns,polar groups, length of hydrogen bonds and hydrophobicity of the Presenilin ۱ protein. Theresults of Poly Phen-۲ predict scores equal ۱, in the SIFT, scores are less than ۰.۰۵, in theGVGD, they are classified in the class C۶۵ and in the I-Mutant, all ten aforenamed SNPs arepathogens that their stabilities decrease and have the most interfere with function of Presenilin ۱protein.Conclusion: According to in-silico assays, all of ten mentioned SNPs can be harmful although itshould be noted that in-silico methods have their own advantages and limitations and their resultsare predictions which require confirmation.

کلیدواژه ها:

AD ، PSEN۱ ، nsSNP ، Structure prediction ، Pathogenicity