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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Identification of a Pathogenic PSEN1 Ala285Val Mutation Associated with Early-Onset Alzheimer’s Disease

Author(s): Van Giau Vo, Jung-Min Pyun, Eva Bagyinszky, Seong S.A. An* and Sang Y. Kim*

Volume 17, Issue 5, 2020

Page: [438 - 445] Pages: 8

DOI: 10.2174/1567205017666200626210727

Price: $65


Background: Presenilin 1 (PSEN1) was suggested as the most common causative gene of early onset Alzheimer’s Disease (AD).

Methods: Patient who presented progressive memory decline in her 40s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using whole exome sequencing. The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs.

Results: A pathogenic mutation in PSEN1 (NM_000021.3: c.1027T>C p.Ala285Val), which was found in a Korean EOAD patient. Magnetic resonance imaging scan showed mild left temporal lobe atrophy. Hypometabolism appeared through 18F-fludeoxyglucose Positron Emission Tomography (FDG-PET) scanning in bilateral temporal and parietal lobe, and 18F-Florbetaben-PET (FBB-PET) showed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and hence presumed preclinical AD. Protein modeling showed that the p.Ala285Val is located in the random coil region and could result in extra stress in this region, resulting in the replacement of an alanine residue with a valine. This prediction was confirmed previous in vitro studies that the p.Trp165Cys resulted in an elevated Aβ42/Aβ40 ratio in both COS-1 and HEK293 cell lines compared that of wild-type control.

Conclusion: Together, the clinical characteristics and the effect of the mutation would facilitate our understanding of PSEN1 in AD pathogenesis for the disease diagnosis and treatment. Future in vivo study is needed to evaluate the role of PSEN1 p.Ala285Val mutation in AD progression.

Keywords: Alzheimer`s disease, PSEN1, p.Ala285Val, genetics, mutation, neurodegenerative genes.

Giau VV, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Sci Rep 2019; 9(1): 8368.
[] [PMID: 31182772]
Giau VV, Senanarong V, Bagyinszky E, An SSA, Kim S. Analysis of 50 neurodegenerative genes in clinically diagnosed early-onset Alzheimer’s disease. Int J Mol Sci 2019; 20(6) E1514
[] [PMID: 30917570]
Giau VV, Bagyinszky E, Youn YC, An SSA, Kim S. APP, PSEN1, and PSEN2 mutations in asian patients with early-onset Alzheimer disease. Int J Mol Sci 2019; 20(19) E4757
[] [PMID: 31557888]
Giau VV, Lee H, Shim KH, Bagyinszky E, An SSA. Genome-editing applications of CRISPR-Cas9 to promote in vitro studies of Alzheimer’s disease. Clin Interv Aging 2018; 13: 221-33.
[] [PMID: 29445268]
Van der Flier WM. Clinical heterogeneity in familial Alzheimer’s disease. Lancet Neurol 2016; 15(13): 1296-8.
[] [PMID: 27777021]
Ryman DC, Acosta-Baena N, Aisen PS, et al. Dominantly inherited Alzheimer network. Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis. Neurology 2014; 83(3): 253-60.
[] [PMID: 24928124]
Giau VV, Wang MJ, Bagyinszky E, Youn YC, An SSA, Kim S. Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer’s disease with parkinsonism. Neurobiol Aging 2018; 72: 188.e13-7.
[] [PMID: 30180983]
Senanarong V, An SSA, Vo Van G, Limwongse C, Bagyinszky E, Kim S. Pathogenic PSEN1 Glu184Gly mutation in a family from Thailand with probable autosomal dominant early onset Alzheimer’s disease. Diagnostics (Basel) 2020; 10(3): 135.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA 2017; 114(4): E476-85.
[] [PMID: 27930341]
Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996; 17(5): 1005-13.
[] [PMID: 8938131]
Murayama O, Tomita T, Nihonmatsu N, et al. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett 1999; 265(1): 61-3.
[] [PMID: 10327206]
Xia D, Watanabe H, Wu B, et al. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease. Neuron 2015; 85(5): 967-81.
[] [PMID: 25741723]
Giau VV, Bagyinszky E, An SSA, Kim S. Clinical genetic strategies for early onset neurodegenerative diseases. Mol Cell Toxicol 2018; 14(2): 123-42.
Ikeda M, Sharma V, Sumi SM, et al. The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol 1996; 40(6): 912-7.
[] [PMID: 9007097]
Aoki M, Abe K, Oda N, et al. A presenilin-1 mutation in a Japanese family with Alzheimer’s disease and distinctive abnormalities on cranial MRI. Neurology 1997; 48(4): 1118-20.
[] [PMID: 9109915]
Page RM, Baumann K, Tomioka M, et al. Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem 2008; 283(2): 677-83.
[] [PMID: 17962197]
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34(7): 939-9.
Van Giau V, An SSA, Bagyinszky E, Kim S. Gene panels and primers for next generation sequencing studies on neurodegenerative disorders. Mol Cell Toxicol 2015; 11(2): 89-143.
Källberg M, Wang H, Wang S, et al. Template-based protein structure modeling using the RaptorX web server. Nat Protoc 2012; 7(8): 1511-22.
[] [PMID: 22814390]
Ch’ng GS, An SS, Bae SO, Bagyinszky E, Kim S. Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. Neuropsychiatr Dis Treat 2015; 11: 2315-22.
[PMID: 26396515]
Hamaguchi T, Morinaga A, Tsukie T, Kuwano R, Yamada M. A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease. J Neurol 2009; 256(9): 1575-7.
[] [PMID: 19430857]
Aldudo J, Bullido MJ, Arbizu T, Oliva R, Valdivieso F. Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer’s disease. Neurosci Lett 1998; 240(3): 174-6.
[] [PMID: 9502232]
Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: A case series. Lancet Neurol 2016; 15(13): 1326-35.
[] [PMID: 27777022]
Clark RF, Hutton M, Fuldner M, et al. Alzheimer’s Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 1995; 11(2): 219-22.
[] [PMID: 7550356]
Dermaut B, Kumar-Singh S, De Jonghe C, et al. Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer’s disease due to a novel presenilin 1 mutation. Brain 2001; 124(Pt 12): 2383-92.
[] [PMID: 11701593]
Hiltunen M, Helisalmi S, Mannermaa A, et al. Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer’s disease family: An Alu core sequence-stimulated recombination? Eur J Hum Genet 2000; 8(4): 259-66.
[] [PMID: 10854108]
Le Guennec K, Veugelen S, Quenez O, et al. Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds. Neurobiol Dis 2017; 104: 97-103.
[] [PMID: 28461250]
Lam B, Khan A, Keith J, et al. Characterizing familial corticobasal syndrome due to Alzheimer’s disease pathology and PSEN1 mutations. Alzheimers Dement 2017; 13(5): 520-30.
[] [PMID: 27743520]
Sánchez-Valle R, Lladó A, Ezquerra M, Rey MJ, Rami L, Molinuevo JL. A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas. Eur J Neurol 2007; 14(12): 1409-12.
[] [PMID: 18028191]
Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M. Alzheimer’s disease with spastic paresis and cotton wool type plaques. J Neurosci Res 2002; 70(3): 367-72.
[] [PMID: 12391599]
Marrosu MG, Floris G, Costa G, et al. Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology 2006; 66(1): 108-11.
[] [PMID: 16401857]
Dumanchin C, Tournier I, Martin C, et al. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat 2006; 27(10): 1063-3.
[] [PMID: 16941492]
Ikeuchi T, Kaneko H, Miyashita A, et al. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord 2008; 26(1): 43-9.
[] [PMID: 18587238]
Wanngren J, Frånberg J, Svensson AI, et al. The large hydrophilic loop of presenilin 1 is important for regulating gamma secretase complex assembly and dictating the amyloid beta peptide (Abeta) Profile without affecting Notch processing. J Biol Chem 2010; 285(12): 8527-36.
[] [PMID: 20106965 ]

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