Screening For Mutations In The Coding Regions Of PSEN1 Gene, 16-17 Exons Of APP Gene And APOE Genotyping In Patients With Alzheimer’s Disease

Year 2020, , 35 - 41, 18.06.2020

Tugce Karaduman

https://doi.org/10.46810/tdfd.713624

Cited By: 1

Abstract

The aim of this study is to screen for mutations in the presenilin-1 (PSEN1) gene,16-17 exons of amyloid precursor protein (APP) gene and determining apolipoprotein-E (APOE) genotype in patients with Alzheimer’s disease (AD). The coding regions of PSEN1 gene, 16-17 exons of APP gene were screened by using DNA sequence analysis in 30 patients with late onset of Alzheimer’s disease (LOAD) diagnosed based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and 40 non-dementia controls. Additionally, genotype and allele frequencies of ε2, ε3 and ε4 polymorphisms of APOE gene were determined by using PCR-RFLP methods in both groups. No mutation was found in the coding regions of PSEN1 gene and 16-17 exons of APP gene. On the other hand, rs165932 (G/T) polymorphism was found in intron 8 of PSEN1 in 26 patients. There was no significant difference in genotype and allele frequencies of intronic polymorphism between control group and patients (p>0.05). The frequency of ε3/ε4 genotype was significantly higher in patient group (p<0.05) and frequencies of ε4 allele were also significantly higher among the patients with LOAD (p<0.05). When PSEN1 genotype distribution and ε4 allele frequency were evaluated together in the patient group, no significant relation was found (p>0.05). We suggested that there was a potential association between LOAD and APOE ε4 allele; however, no result could found to link the between PSEN1 gene polymorphism and disease pathogenesis.

Keywords

Alzheimer’s disease, polymorphism, mutation, PSEN1, APP, APOE

Thanks

This work was supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK), Grant: 2210-E and Hacettepe University Teaching Staff Training Programme (OYP) Office.

Alzheimer Hastalarında PSEN1 Geni Kodlayan Bölgelerinde ve APP Geni 16-17. Ekzonlarında Mutasyon Taraması ve APOE Genotiplendirmesi

Abstract

Bu çalışmanın amacı, Alzheimer hastalarında (AD) presenilin-1 (PSEN1) geninin tüm ekzonları ve amiloid precursor protein (APP) geni 16-17. ekzonlarında mutasyon taraması gerçekleştirmek ve hastaların apolipoprotein-E (APOE) genotipini belirlemektir. PSEN1 geni tüm ekzonları ve APP geni 16-17.ekzonları, DSM-IV kriterlerine göre teşhis edilen 30 geç başlangıçlı Alzheimer hastası bireyde (GBAH) ve 40 demans tanısı bulunmayan kontrol bireyde DNA dizi analizi ile taranmıştır. Εk olarak, APOE genine ait ε2, ε3 ve ε4 polimorfizmlerinin genotip ve allel frekansları her iki grupta PZR-RFLP methodu kullanılarak belirlenmiştir. PSEN1 geni kodlayan bölgelerinde ve APP geni 16-17.ekzonlarında herhangi bir mutasyona rastlanılamamıştır. Ancak 26 hastada PSEN1 geni intron 8 bölgesinde rs165932 (G/T) polimorfizmi tespit edilmiştir. Bununla birlikte intronik polimorfizmin, genotip ve allel frekansları açısından kontrol ve hasta grupları arasında anlamlı bir fark bulunamamıştır (p>0.05). APOE ε3/ε4 genotipi hasta grubunda önemli derecede yüksek oranda iken (p<0.05) ε4 alel frekansı GBAH olgularında anlamlı derecede yüksek bulunmuştur. Hasta grubunda PSEN1 genotip dağılımı ve ε4 alel frekansı birlikte değerlendirildiğinde anlamlı bir ilişki bulunamamıştır (p>0.05). Çalışmamızda, GBAH ve ε4 alel frekansı arasında önemli bir ilişki olduğu belirlenirken, PSEN1 geni rs165932 (G/T) polimorfizmi ve hastalık patogenezi arasında herhangi bir ilişki bulunamamıştır.

Keywords

Alzheimer hastalığı, polimorfizm, mutasyon, PSEN1, APP, APOE

References

• [1] St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC et al. The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 1987; 235 (4791) :885-890.
• [2] Nuo-Min L, Ke-Fu L, Yun-Jie Q, Huan-Huan Z, Hiroshi N, Hong Q. Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer’s disease pathogenesis. Neural Regen Research. 2019;14(4):658-665.
• [3] Thomas W, Divyakolu S, Sreekanth VR, Vallomkonda VRO, Vallomkonda N, Qurratulain H et al. Variations in Hotspot Region of β-amyloid Precursor Protein (APP) Gene in Various Neurological Disorders from Hyderabad, a Cosmopolitan City of South India. Int J Clin and Exp Neurol 2015; 3(1) :4-10.
• [4] Chandak GR, Sridevi MU, Vas CJ, Panikker DM, Singh L. Apolipoprotein E and presenilin-1 allelic variation and Alzheimer's disease in India. Hum Biol 2002; 74(5) :683-693.
• [5] Giau VV, Pyun JM, Suh J, Bagyinszky E, An SSA and Kim SY. A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease. BMC Neurology. 2019; 19:188 https://doi.org/10.1186/s12883-019-1419-y.
• [6] Zhou X, Miao H, Rausch WD, Long M, Luo X, Yu H et al. Association between apolipoprotein Ε gene polymorphism and Alzheimer’s disease in Uighur and Han populations. Psychogeriatrics 2012;12 :83-87.
• [7] Rassas AA, Fredj SH, Khiari HM, Sahnoun S, Bibi A, Siala H et al. No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a Tunisian population. J Neuro Transm 2013; 120(9) :1355-1358.
• [8] Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein Ε by gene amplification and cleveage with HhaI. J Lipid Res 1990; 31 :545-554.
• [9] Borges MK, Lopes TN, Biella MM, Siqueira A, Mauer S and Aprahamian I. Early-Onset Alzheimer Disease (EOAD) With Aphasia: A Case Report. Front Psychiatry 2018; 9: 469. doi: 10.3389/fpsyt.2018.00469.
• [10] Strooper DB. Loss-of-function presenilin mutations in Alzheimer disease. EMBO reports 2007; 8(2): 141-146.
• [11] Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D et al. The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers. PLoS Genetics 2013; 9(8):e1003685.
• [12] Borghi R, Piccini A, Barini E, Cirmena G, Guglielmotto M, Tamagno E et al. Upregulation of presenilin 1 in brains of sporadic, late-onset Alzheimer's disease. J Alzheimers Dis 2010; 22(3) :771-775.
• [13] Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One 2012; 7(2):e31039.
• [14] Larner AJ, Ray PS, Doran M. The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neuro Sci 2007; 252(2) :173-176. [15] Wahlster L, Arimon M, Nasser-Ghodsi N, Post KL, Serrano-Pozo A, Uemura K et al. Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease. Acta Neuropathol 2013;125(2) :187-199.
• [16] Anwar R, Moynihan TP, Ardley H, Brindle N, Coletta PL, Cairns N et al. Molecular analysis of the presenilin1 (S182) gene in “sporadic” cases of Alzheimer’s disease: identification and charecterisation of unusual splice variants. J Neurochem 1996; 66(4) :1774-1777.
• [17] Gerrish A, Russo G, Richards A, Moskvina V, Ivanov D, Harold D, The role of variation at AβPP, PSEN1, PSEN2 and MAPT in late onset Alzheimer’s disease. J Alzheimer’s Dis 2012; 28(2): 377-387.
• [18] Matsushita S, Arai H, Muramatsu T, Makimoto K, Nakagawa T, Sasaki H et al. Presenilin-1 polymorphism and Alzheimer’s Disease. Lancet 1996; 347 :1185-1186.
• [19] Rodríguez-Manotas M, Amorín-Díaz M, Cañizares-Hernández F, Ruíz-Espejo F, Martínez-Vidal S, González-Sarmiento R et al. Association study and meta-analysis of Alzheimer's disease risk and presenilin-1 intronic polymorphism, Brain Res 2007;19;1170 :119-128.
• [20] Wragg M, Hutton M, Talbot C, and the Alzheimer's Disease Collaborative Group, Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer’s disease, Lancet 1996; 347 :509-512.
• [21] Arango D, Cruts M, Torres O, Backhovens H, Serrano ML, Villareal E et al. Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia, Am J Med Genet 2001;103 :138–143.
• [22] Houlden H, Crawford F, Rossor M, Mullan M. Screening for the APP codon 670/671 mutations in Alzheimer’s disease. Neurosci Lett 1993; 154 :161–162.
• [23] Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM et al. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet 1992; 51 :998–1014.
• [24] Tanzi ER, Vaula G, Romano DM., Mortilla M, Huang TL, Tupler RG et al. Assessment of amyloid beta-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am J Hum Genet 1992; 51 :273–282.
• [25] Rassas AA, Mrabet Khiari H, Hadj Fredj S, Sahnoun S, Batti H, Zakraoui NO et al. High APOE epsilon 4 allele frequencies associated with Alzheimer disease in a Tunisian population. Neurol Sci 2012; 33(1): 33-37.
• [26] Yokeş MB, Apolipoprotein Ε Genotyping in Turkish Alzheimer Patients. Balkan J Med Genet 2007; 8(1) :57-63.
• [27] Cannon-Albright LA, Foster NL, Schliep K, Farnham JM, Teerlink CC, Kaddas H, et al. Relative risk for Alzheimer disease based on complete family history. Neurology 2019; (92): 1745-1753. doi:10.1212/WNL.0000000000007231.
• [28] Talboom JS, Håberg A De Both MW, Naymik MA, Schrauwen I, Lewis CR, et al. Family history of Alzheimer’s disease alters cognition and is modified by medical and genetic factors. eLife. 2019; (8): e46179. doi: 10.7554/eLife.46179.
• [29] Haussmann R, Ganske S, Gruschwitz A, Werner A, Osterrath A, Lange J et al. Family History of Alzheimer’s Disease and Subjective Memory Performance. Am J Alzheımers Dıs 2018; 33(7):153331751877503 doi: 10.1177/1533317518775033.
• [30] Singleton AB, Lamb H, Leake A, McKeith IG, Perry RH, Morris CM. No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a German population. J Neuro Sci 1999; 167(1) :34-36.
• [31] B.V.P. de-Almada, L.D. de-Almeida, D. Camporez, M.V.D. de-Moraes, R.L. Morelato, A.M.S. Perrone et al. Protective effect of the APOE-e3 allele in Alzheimer’s disease. Braz J Med and Biol Res 2012; 45 (1) 8-12.
• [32] Hu CJ, Sung SM, Liu HC, Chang JG. Association of apolipoprotein E genotype and intronic polymorphism of the presenilin-1 gene with Alzheimer's disease in elderly Taiwan Chinese. J Neuro Sci 1998; 157(2) :158-161.